Fluconazole by Golden State Medical Supply, Inc. / Aphena Pharma Solutions - Tennessee, LLC / ANI Pharmaceuticals Canada, Inc. FLUCONAZOLE tablet

Fluconazole by

Drug Labeling and Warnings

Fluconazole by is a Prescription medication manufactured, distributed, or labeled by Golden State Medical Supply, Inc., Aphena Pharma Solutions - Tennessee, LLC, ANI Pharmaceuticals Canada, Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

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DESCRIPTION

Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration.

Fluconazole is designated chemically as 2,4-difluoro-α,α 1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C 13H 12F 2N 6O and molecular weight of 306.3. The structural formula is:

Fluconazole is a white crystalline solid which is slightly soluble in water and saline.

Each fluconazole tablet, USP contains either 50 mg, 100 mg, 150 mg, or 200 mg of fluconazole and the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, FD&C Red No. 40 aluminum lake, magnesium stearate, microcrystalline cellulose and povidone.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (C max) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C max of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are dose proportional.

The C max and AUC data from a food-effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole tablets may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.)

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11% to 12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid: plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

Tissue or Fluid	Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration*
* Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation.
Cerebrospinal fluid †	0.5 to 0.9
Saliva	1
Sputum	1
Blister fluid	1
Urine	10
Normal skin	10
Nails	1
Blister skin	2
Vaginal tissue	1
Vaginal fluid	0.4 to 0.7

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations and the adrenocorticotropic hormone (ACTH)-stimulated cortisol response.

Pharmacokinetics in Children

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

Age Studied	Dose (mg/kg)	Clearance (mL/min/kg)	Half-life (Hours)	C max (mcg/mL)	Vdss (L/kg)
9 Months to 13 years	Single-Oral; 2 mg/kg	0.40 (38%); N=14	25.0	2.9 (22%); N=16	—
9 Months to 13 years	Single-Oral; 8 mg/kg	0.51 (60%); N=15	19.5	9.8 (20%); N=15	—
5 to 15 years	Multiple IV; 2 mg/kg	0.49 (40%); N=4	17.4	5.5 (25%); N=5	0.722 (36%); N=4
5 to 15 years	Multiple IV; 4 mg/kg	0.59 (64%); N=5	15.2	11.4 (44%); N=6	0.729 (33%); N=5
5 to 15 years	Multiple IV; 8 mg/kg	0.66 (31%); N=7	17.6	14.1 (22%); N=8	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.

Pharmacokinetics in Elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The C max 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 C max. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0 to 24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-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

(See PRECAUTIONS, Drug Interactions)

Oral contraceptives

Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 50 mg once daily for 10 days in 10 healthy women.

There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The mean increase in ethinyl estradiol AUC was 6% (range: –47% to 108%) and levonorgestrel AUC increased 17% (range: –33% to 141%).

In a second study, twenty-five normal females received daily doses of both 200 mg fluconazole tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12% to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11% to 101%). Both of these increases were statistically significantly different from placebo.

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

Cimetidine

Fluconazole 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and C max. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4% to –31%) and C max decreased 19% ± 14% (range: –5% to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.

Antacid

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

Hydrochlorothiazide

Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and C max compared to fluconazole given alone. There was a mean ± SD increase in fluconazole AUC and C max of 45% ± 31% (range: 19% to 114%) and 43% ± 31% (range: 19% to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10% to –50%).

Rifampin

Administration of a single oral 200 mg dose of fluconazole after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13% to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16% to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)

Warfarin

There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral fluconazole 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2% to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response.

Phenytoin

Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16% to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.)

Cyclosporine

Cyclosporine AUC and C max were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, C max, C min (24-hour concentration) and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18% to 147%). The C max increased 60% ± 48% (range: –5% to 133%). The C min increased 157% ± 96% (range: 33% to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15% to –60%). (See PRECAUTIONS.)

Zidovudine

Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27% to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.

Theophylline

The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, C max, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5% to 48%). The C max increased 13% ± 17% (range: –13% to 40%). Theophylline clearance decreased 16% ± 11% (range: –32% to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.)

Terfenadine

Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7% to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg 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 fluconazole 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of fluconazole treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.)

Tolbutamide

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

Glipizide

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

Glyburide

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

Rifabutin

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

Tacrolimus

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

Cisapride

A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride C max. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride C max. 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 C max by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and C max by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam.

A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and C max of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and C max by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and C max by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.)

Azithromycin

An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Voriconazole

Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in C max and AUC τ 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 to 7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in increased mean tofacitinib AUC and C max values of approximately 79% (90% CI: 64% to 96%) and 27% (90% CI: 12% to 44%), respectively, compared to administration of tofacitinib alone. (See PRECAUTIONS)

Microbiology

Mechanism of Action

Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.

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.

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 mcg/mL), the highest fluconazole dose is recommended.

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

Antimicrobial Activity

Fluconazole has been shown to be active against most 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

The following in vitro data are available, but their clinical significance is unknown. At lease 90% of the following fungi exhibit an in vitro MIC less than or equal to the susceptible breakpoint for fluconazole (https://www.fda.gov/STIC) against isolates of similar genus or organism group. However, the effectiveness of fluconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials.

Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei ). Such cases may require alternative antifungal therapy.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

INDICATIONS AND USAGE

Fluconazole tablets, USP are indicated for the treatment of:

1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole tablets, USP were also effective for the treatment of Candida urinary tract infections, peritonitis and systemic Candida infections including candidemia, disseminated candidiasis and pneumonia.
3. Cryptococcal meningitis. Before prescribing fluconazole tablets, USP for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole to amphotericin B in non-HIV infected patients have not been conducted.

Prophylaxis. Fluconazole tablets, USP are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

CLINICAL STUDIES

Cryptococcal meningitis

In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm 3. Mortality among high risk patients was 33% and 40% for amphotericin B and fluconazole patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.)

Vaginal candidiasis

Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation.

The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group.

	Fluconazole PO 150 mg tablet	Vaginal Product qhs × 7 days
Enrolled	448	422
Evaluable at Late Follow-up	347 (77%)	327 (77%)
Clinical cure	239/347 (69%)	235/327 (72%)
Mycologic eradication	213/347 (61%)	196/327 (60%)
Therapeutic cure	190/347 (55%)	179/327 (55%)

Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when treated with a 150 mg fluconazole tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis.

Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred.

Parameter	Fluconazole PO	Vaginal Products
Evaluable patients	448	422
With any adverse event	141 (31%)	112 (27%)
Nervous System	90 (20%)	69 (16%)
Gastrointestinal	73 (16%)	18 (4%)
With drug-related event	117 (26%)	67 (16%)
Nervous System	61 (14%)	29 (7%)
Headache	58 (13%)	28 (7%)
Gastrointestinal	68 (15%)	13 (3%)
Abdominal pain	25 (6%)	7 (2%)
Nausea	30 (7%)	3 (1%)
Diarrhea	12 (3%)	2 (<1%)
Application site event	0 (0%)	19 (5%)
Taste Perversion	6 (1%)	0 (0%)

Pediatric Studies

Oropharyngeal candidiasis

An open-label, comparative study of the efficacy and safety of fluconazole (2 to 3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole.

Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients.

	Fluconazole	Nystatin
* Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response.
Enrolled	96	90
Clinical Cure	76/88 (86%)	36/78 (46%)
Mycological eradication *	55/72 (76%)	6/54 (11%)

The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving fluconazole and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment the percentages of patients with clinical relapse were 22% for fluconazole and 23% for nystatin.

CONTRAINDICATIONS

Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)

WARNINGS

(1) Hepatic injury

Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole.

(2) Anaphylaxis

In rare cases, anaphylaxis has been reported.

(3) Dermatologic

Exfoliative skin disorders during treatment with fluconazole have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

(4) Potential for fetal harm

There are no adequate and well-controlled clinical trials of fluconazole in pregnant women. Case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with fluconazole 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dosage. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. (See PRECAUTIONS: Pregnancy)

PRECAUTIONS

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. (See PRECAUTIONS: Drug Interactions.) During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsades de pointes.

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

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided.

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

Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole. Reversible cases of adrenal insufficiency have been reported in patients receiving fluconazole.

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

Single Dose

The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with fluconazole (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.)

Drug Interactions

(See CONTRAINDICATIONS.) Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with this drug, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed / documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed and are described in greater detail below:

Alfentanil

A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amiodarone

Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800mg).

Amitriptyline, nortriptyline

Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/ nortriptyline should be adjusted, if necessary.

Amphotericin B

Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with 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.

Astemizole

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Azithromycin

An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Calcium Channel Blockers

Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Carbamazepine

Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Celecoxib

During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Cisapride

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

(See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Coumarin-type anticoagulants

Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Cyclophosphamide

Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Cyclosporine

Fluconazole significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Fentanyl

One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA reductase inhibitors

The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Hydrochlorothiazide

In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.

Losartan

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone

Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs

The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Olaparib

Moderate inhibitors of CYP3A4 such as fluconazole increase Olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of Olaparib as instructed in the Olaparib Prescribing information.

Oral Contraceptives

Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Oral hypoglycemics

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

Phenytoin

Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Pimozide

Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Prednisone

There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Quinidine

Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS.)

Rifabutin

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Rifampin

Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Saquinavir

Fluconazole increases the AUC of saquinavir by approximately 50%, C max by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Short-acting Benzodiazepines

Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Sirolimus

Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Tacrolimus

Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Terfenadine

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg 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.

Theophylline

Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving fluconazole and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Tofacitinib

Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the 1XELJANZ ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

1 XELJANZ ® is the registered trademark of Pfizer.

Triazolam

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C max by 20 to 32%, and increases t½ by 25 to 50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Vinca Alkaloids

Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A

Based on a case report in one patient receiving combination therapy with all-transretinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole

Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Zidovudine

Fluconazole increases C max and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.