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Welcome to the website of the Richter-Addo laboratory at the University of Oklahoma. Our work focuses on the biological inorganic chemistry of the simple nitrogen oxides NOx, and we pay special attention to the interactions of these NOx species with heme proteins and model hemes. We combine classical inorganic chemistry with complex protein biochemistry to examine how the iron center in proteins directs the physiological effects of nitrogen oxides. We welcome you to this site!
We are part of the Price Family Foundation Institute of Structural Biology.
Structural Biology of Heme Proteins
We utilize single-crystal macromolecular X-ray diffraction techniques to elucidate the role that Fe plays in the biological chemistry of NOx species. The proteins we normally use are myoglobin (Mb) and hemoglobin (Hb). We have demonstrated unique binding modes for both nitric oxide (NO) and nitrite to these proteins that helps to explain the physiological chemistry that these NOx species display. We use both in-house X-ray diffraction equipment and synchrotron-based (Brookhaven National Laboratory) techniques. More...
Electrochemistry and Spectroelectrochemistry
Electrochemistry is an excellent tool to study the generation and behavior of redox intermediates in chemical reactions. We have developed new methodology to make infrared and UV-vis spectroelectrochemistry more readily available to synthetic chemists. More...
Gas-phase Biomarker Detection
In collaboration with the McCann group in Electrical Engineering, we are developing new TDLAS methodology for the specific and simultaneous detection of nitric oxide (NO), 15-NO, and nitrous oxide (N2O; a nitroxyl dimerization product) from complex biochemical mixtures. More...
We are located in the Stephenson Life Sciences Research Center on the southeast side of the city of Norman.
The Richter-Addo laboratory, Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019. Tel: +1-405-325-2378.
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1. Day at the Science Fair (St. Louis) PDF
2. Radio interview of Dr. Michael Shaw (SIUE), collaborator on NSF Grant on electrochemistry
3. Guest lectures in electrochemistry at Langston University (c/o Dr. Sharron Lewis)
4. Description of the new Stephenson Life Sciences Research Center at OU PDF
5 . Description of the Chemical Zoo at the Stephenson Life Sciences Research Center LINK
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Phone & Email
Learn More »
MSDS Sheets Access
Web Accessibility Checker
Gladysz group website (lab handouts)
KhanAcademy videos on basics (chemistry, math, biology, etc)
JChemEd article on the Names of the Elements
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And, unless I really had no other options, would definitely NOT pretend to be able to fly a plane.
But Captain William Hamman, a senior jumbo jet captain for United Airlines, has apparently been doing both. He really is a pilot.
At the same time (sort of like in Catch Me If You Can) he's been passing himself off as a doctor. Not just any doctor, but a cardiologist. And he's done training courses for the AMA, American College of Caridiology, and FAA. He's done CME lectures at accredited training programs.
Guess what? After many years of doing this, he turns out not to be a doctor at all! He never did residency, or fellowship. He briefly attended medical school in the late 1970's, but dropped out and never graduated.
And it took 30 freakin' years for someone to realize this!
Here's the story.
Thank you, Don.

subset: commoncrawl


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I have a basic working knowledge of category thoery since I do research in programming languages and typed lambda-calculus. Indeed, I have refereed many papers in my area based on category theory.
But, in doing this refereeing, and in reading many important categorial papers in my area, I simply find the terminology and presentation style extremely opaque compared to style that I prefer which instead emphasizes logic inference rules and extensions of the lambda calculus.
Given the (extended) Curry-Howard Isomorphism between programming languages, logics, and categories, it's clear that I can understand the concepts I need by mapping category theory into the other two. But, am I missing something in the process, or are the papers I'm refereeing just making things more difficult than they need to be?


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Ferran Adrià's Chicken Wings with Mushrooms Recipe
Your source for quick recipe every single week day.
I have a soft spot for chicken wings; Ferran Adrià apparently does too. The universally acclaimed Spanish chef is known for his forward thinking cuisine, but his latest cookbook, The Family Meal, which we recently featured in our Cook the Book series, is filled exclusively with the simple staff meals that were served at his restaurant, El Bulli, before it closed this year.
If you're looking for the some mind-bending and ridiculously complex approach to the humble chicken wing, move along. But if you're looking for a straightforward, comforting meal absolutely loaded with garlic then you're in luck.
Instead of being fried, these chicken wings are sautéed over moderate heat for 30 minutes, which turns them crackly and golden brown. Then it's all about adding flavor. Ten garlic cloves are tossed in, along with a bay leaf and sprig of thyme. Mushrooms add a bit of depth, while the wine helps cut through the fat. Roasted potatoes would be the perfect side for this dish.
- Yield:serves 2
- Active time: 1 hour
- Total time:1 hour
- Rated:
- 6 chicken wings, tips discarded, cut into drumettes and flats (12 pieces total)
- salt and black pepper
- 1/4 cup olive oil
- 4 ounces mushrooms (cremeini, white button, or shimeji work) stems removed, caps cut into thick slices
- 10 garlic cloves, chopped
- 1 dried bay leaf
- 1 sprig fresh thyme
- 1/4 cup white wine
- 3 1/2 tablespoons water
Season the chicken wings with salt and black pepper. Pour the oil into a large cast-iron skillet set over medium heat. When oil starts to shimmer, add the chicken wings. Cook, flipping occasionally, until the wings are well browned, about 30 minutes. Reduce the heat to medium-low if the wings brown too quickly.
If you haven't already reduced the heat to medium-low, do so now, and add the chopped garlic. Cook until golden brown, stirring occasionally, about five minutes.
Add the bay leaf and sprig of thyme. Stir well, and let cook for a few seconds. Then pour in the white wine. Turn the heat up to medium-high and let the liquid reduce for a minute or so.
Toss in the mushrooms. Stir well and let cook for two minutes. Then pour in the water, and cook until the liquid has reduced and the mushrooms are tender, about five minutes. Serve immediately.
All products linked here have been independently selected by our editors. We may earn a commission on purchases, as described in our affiliate policy.


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Fluconazole in sodium chloride injection
Spl unclassified section
Fluconazole in Sodium Chloride Injection, USP
For intravenous infusion only
in INTRAVIA Plastic Container
Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as a sterile solution for intravenous use in INTRAVIA plasticcontainer.
Fluconazole is designated chemically as 2,4-difluoro-, 1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C 13H 12F 2N 6O and molecular weight 306.3. The structural formula is:
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
Fluconazole in Sodium Chloride Injection, USP is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride diluent. Each mLcontains 2 mg of fluconazole and 9 mg of sodium chloride. The pH ranges from 4.0 to 6.5. Injection volumes of 100 mL and 200 mL are packaged inINTRAVIA plastic containers.
The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach outcertain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic containermaterials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affectthe premixed solution.
Fluconazole in Sodium Chloride Injection, USP meets USP Organic Impurities Procedure 3.
Clinical pharmacology
Pharmacokinetics and metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, thebioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the100 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 ofapproximately 30 hours (range: 20-50 hours) after oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C maxof 6.72 mcg/mL(range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasmaconcentration-time curve) are dose proportional.
Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean C maxof 2.61 mcg/mL (range: 1.57 to3.65 mcg/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 (onday 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution offluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple oral doses for up to 14days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to orslightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrationsof fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungalmeningitis, 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 from0.94 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 to0.71 over the first 72 hours following dosing.
|Tissue or Fluid
Ratio of Fluconazole
Tissue (Fluid)/Plasma
|Cerebrospinal fluid
|0.5 - 0.9
|Blister fluid
|Normal skin
|Blister skin
|Vaginal tissue
|Vaginal fluid
|0.4 - 0.7
* 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 asunchanged 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-lifeand creatinine clearance. The dose of Fluconazole in Sodium Chloride Injection, USP 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 andinconsistent 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:
|9 Months -
13 years
2 mg/kg
|0.40 (38%)
|2.9 (22%)
|9 Months -
13 years
8 mg/kg
|0.51 (60%)
|9.8 (20%)
|5 - 15 years
|Multiple IV
2 mg/kg
|0.49 (40%)
|5.5 (25%)
|0.722 (36%)
|5 - 15 years
|Multiple IV
4 mg/kg
|0.59 (64%)
|11.4 (44%)
|0.729 (33%)
|5 - 15 years
|Multiple IV
8 mg/kg
|0.66 (31%)
|14.1 (22%)
|1.069 (37%)
Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, whichincreased 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 was73.6 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 patientswere concomitantly receiving diuretics. The C maxwas 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 20.3 mcgh/mL,and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal youngmale volunteers. Coadministration of diuretics did not significantly alter AUC or C max. In addition, creatinine clearance (74 mL/min), the percent of drugrecovered unchanged in urine (0-24 hr, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower thanthose of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristicof this group. A plot of each subjects terminal elimination half-life versus creatinine clearance compared with the predicted half-life creatinineclearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the95% confidence limit of the predicted half-life creatinine clearance curves. These results are consistent with the hypothesis that higher values for thepharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney functionthat 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 fluconazole 50 mg once daily for 10 days in 10healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The meanincrease 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. Thetreatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of studytreatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the finaltreatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrelcompared 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 contraceptivecontaining ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over threecycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone comparedto 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 subjectin this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects afterfluconazole treatment.
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 fluconazoleAUC of 13% 11% (range: -3.4 to -31%) and C maxdecreased 19% 14% (range: -5 to -40%). However, the administration of cimetidine 600 mg to900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of fluconazole200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.
Administration of MAALOX antacid (20 mL) to 14 normal male volunteers immediately prior to a single dose of fluconazole 100 mg had no effect on theabsorption or elimination of fluconazole.
Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significantincrease in fluconazole AUC and C maxcompared to fluconazole given alone. There was a mean SD increase in fluconazole AUC and C maxof45% 31% (range: 19 to 114%) and 43% 31% (range: 19 to 122%), respectively. These changes are attributed to a mean SD reduction in renalclearance of 30% 12% (range: -10 to -50%).
Administration of a single oral 200 mg dose of fluconazole after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteersresulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean SDreduction 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 .)
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 administrationof 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 hisprothrombin time response.
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) bothwith and without the administration of fluconazole (oral fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significantincrease in phenytoin AUC. The mean SD increase in phenytoin AUC was 88% 68% (range: 16 to 247%). The absolute magnitude of this interactionis unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS .)
Cyclosporine AUC and C maxwere determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplantpatients 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 significantincrease in cyclosporine AUC, C max, C min(24-hour concentration), and a significant reduction in apparent oral clearance following the administrationof fluconazole. The mean SD increase in AUC was 92% 43% (range: 18 to 147%). The C maxincreased 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 .)
Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteerswith AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following theadministration of fluconazole. The mean SD increase in AUC was 20% 32% (range: -27 to 104%). The metabolite, GZDV, to parent drug ratiosignificantly decreased after the administration of fluconazole, from 7.6 3.6 to 5.7 2.2.
The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oraladministration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, C max, andhalf-life with a corresponding decrease in clearance. The mean SD theophylline AUC increased 21% 16% (range: -5 to 48%). The C maxincreased13% 17% (range: -13 to 40%). Theophylline clearance decreased 16% 11% (range: -32 to 5%). The half-life of theophylline increased from6.6 1.7 hours to 7.9 1.5 hours. (See PRECAUTIONS .)
Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazoledid not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% 36% (range: 7 to 102%) from day 8 to day 15 withthe concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasmalevels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS .)
Although not studied in vitroor in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Useof quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine iscontraindicated. (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 inthree placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose followingthe 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%) ofplacebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS .)
In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and C maxfollowing the administration offluconazole. There was a mean SD increase in tolbutamide AUC of 26% 9% (range: 12 to 39%). Tolbutamide C maxincreased 11% 9% (range: -6to 27%). (See PRECAUTIONS .)
The AUC and C maxof glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal malevolunteers. There was a mean SD increase in AUC of 49% 13% (range: 27 to 73%) and an increase in C maxof 19% 23% (range: -11 to 79%).(See PRECAUTIONS .)
The AUC and C maxof glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal malevolunteers. There was a mean SD increase in AUC of 44% 29% (range: -13 to 115%) and C maxincreased 19% 19% (range: -23 to 62%). Fivesubjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS .)
There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serumlevels of rifabutin. (See PRECAUTIONS .)
There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serumlevels of tacrolimus. (See PRECAUTIONS .)
A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normalsubjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebodosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride C max. Followingmultiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride C max. Fluconazole significantlyincreased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS .)
The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12volunteers. 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, a7.5 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 onthe sixth day. Fluconazole reduced the clearance of intravenous midazolam by 51%. On the first day of dosing, fluconazole increased the midazolamAUC and C maxby 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and C maxby 259% and 74%,respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affectedfollowing intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route ofadministration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg andintravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and intravenous saline. An oral dose of 7.5 mg of midazolamwas ingested after fluconazole/placebo. The AUC and C maxof midazolam were significantly higher after oral than intravenous administration offluconazole. Oral fluconazole increased the midazolam AUC and C maxby 272% and 129%, respectively. Intravenous fluconazole increased themidazolam AUC and C maxby 244% and 79%, respectively. Both oral and intravenous fluconazole increased the pharmacodynamic effects ofmidazolam. (See PRECAUTIONS .)
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 thepharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. Therewas no significant pharmacokinetic interaction between fluconazole and azithromycin.
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 anincrease in C maxand AUC of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-onclinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish thiseffect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events relatedto voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24h of the last dose of fluconazole. (See PRECAUTIONS .)
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) inhealthy subjects resulted in increased mean tofacitinib AUC and C maxvalues of approximately 79% (90% CI: 64% 96%) and 27% (90% CI: 12% 44%), respectively, compared to administration of tofacitinib alone. (See PRECAUTIONS .)
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14--demethylase. This enzyme functions to convertlanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14--methyl sterols in fungi and may be responsiblefor the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.
Drug resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14--demethylase), reduced access tothe 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 ERG11results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibitall of the enzyme molecules in the cell. The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell throughthe activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDRgenes) and those of the ATP-binding cassettesuperfamily (encoded by CDRgenes). Upregulation of the MDRgene leads to fluconazole resistance, whereas, upregulation of CDRgenes may lead toresistance to multiple azoles.
Resistance in Candida glabratausually includes upregulation of CDRgenes resulting in resistance to multiple azoles. For an isolate where the MIC iscategorized as Intermediate (16 to 32 mcg/mL), the highest fluconazole dose is recommended.
Candida kruseishould be considered to be resistant to fluconazole. Resistance in C. kruseiappears to be mediated by reduced sensitivity of the targetenzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candidaspecies other than C. albicans, which are often inherently not susceptible to fluconazole(e.g., Candida krusei). Such cases may require alternative antifungal therapy.
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 MIC 90values against C. glabratawere above the susceptible breakpoint (16 mcg/mL). Resistance in Candida glabratausually includes upregulation of CDRgenes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate(16 to 32 mcg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION ). For resistant isolates, alternative therapy isrecommended.
The following in vitrodata are available, but their clinical significance is unknown.
Fluconazole exhibits in vitrominimum inhibitory concentrations (MIC values) of 8 mcg/mL or less against most (90%) strains of the followingmicroorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not beenestablished in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida kruseishould be considered to be resistant to fluconazole. Resistance in C. kruseiappears to be mediated by reduced sensitivity of the targetenzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candidaspecies 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 methods
Cryptococcus neoformansand filamentous fungi
No interpretive criteria have been established for Cryptococcus neoformansand 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 Candidaspp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth) 1with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided inTable 1.
Diffusion Techniques
Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candidaspp. to anantifungal agent. One such standardized procedure 2requires the use of standardized inoculum concentrations. This procedure uses paper disksimpregnated with 25 mcg 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
(MIC in mcg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
|Antifungal agent
|Susceptible (S)
|Intermediate (I)*
|Resistant (R)
|Susceptible (S)
|Intermediate (I)*
|Resistant (R)
|15 18
|* The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole.
Isolates of C. kruseiare assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale.
The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommendeddosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugsare physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usuallyachievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shownin 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 mcg disks should provide the following range of values noted in Table 2. NOTE: Quality controlmicroorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expressionwithin 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
(MIC in mcg/mL)
@ 48 hours
(MIC in mcg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
|Candida parapsilosisATCC 22019
|Candida kruseiATCC 6258
|Candida albicansATCC 90028
|Candida tropicalisATCC 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.
Indications and usage
Fluconazole in Sodium Chloride Injection, USP is indicated for the treatment of:
- Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole was also effective for the treatment of
Candidaurinary tract infections, peritonitis, and systemic
Candidainfections including candidemia,disseminated candidiasis, and pneumonia.
- Cryptococcal meningitis. Before prescribing Fluconazole in Sodium Chloride Injection, 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 in Sodium Chloride Injection, USP is also indicated to decrease the incidence of candidiasis in patients undergoing bonemarrow 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 identifycausative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these resultsbecome 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 patientswith 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. Mortalityamong high risk patients was 33% and 40% for amphotericin B and fluconazole patients, respectively (p=0.58), with overall deaths 14% (9 of 63subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcalmeningitis and at high risk for treatment failure remain to be determined. (Saag, et al.N Engl J Med 1992; 326:83-9.)
Pediatric Studies
Oropharyngeal candidiasis
An open-label, comparative study of the efficacy and safety of fluconazole (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) inimmunocompromised 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.
|Clinical Cure
|76/88 (86%)
|36/78 (46%)
|Mycological eradication*
|55/72 (76%)
|6/54 (11%)
|*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 fluconazole and 16% for subjectsreceiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for fluconazole and 23% for nystatin.
Fluconazole in Sodium Chloride Injection, USP 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 prescribingFluconazole in Sodium Chloride Injection, USP to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated inpatients receiving Fluconazole in Sodium Chloride Injection, USP at multiple doses of 400 mg or higher based upon results of a multiple dose interactionstudy. 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 .)
(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 in Sodium Chloride Injection, USP therapy should be monitored for the development of more severe hepatic injury. Fluconazole in Sodium Chloride Injection, USP 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 withserious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with Fluconazole in Sodium ChlorideInjection, USP should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated forsuperficial fungal infection who develop a rash that may be attributed to fluconazole.
(4) Use in Pregnancy: There are no adequate and well-controlled studies of fluconazole in pregnant women. Available human data do not suggest anincreased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinctcongenital anomalies in infants exposed in uteroto high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. Thesereported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking thedrug, the patient should be informed of the potential hazard to the fetus (See PRECAUTIONS, Pregnancy .)
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketingsurveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involvedseriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications thatmay have been contributory.
Fluconazole in Sodium Chloride Injection, USP 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) andconsequently sudden heart death. This combination should be avoided.
Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with anarrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored.
Drug interactions
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS .) Fluconazole is a potent inhibitor of cytochrome P450(CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed/documented interactions mentioned below, there is a risk ofincreased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution shouldbe exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions betweenfluconazole and the following agents/classes have been observed. These are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Short-acting benzodiazepines
Oral Contraceptives
Amitriptyline, nortriptyline
Amphotericin B
Calcium Channel Blockers
HMG-CoA reductase inhibitors
Non-steroidal anti-inflammatory drugs
Vinca Alkaloids
Vitamin A
Oral hypoglycemics
Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported fromhypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizideand increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemicagents, 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 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 inassociation with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin timein patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole andphenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Fluconazole significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporineconcentrations 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.
Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given toincreasing the dose of fluconazole when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receivingfluconazole and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals inconjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate aprolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Thecoadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.
There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. Acontrolled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisaprideplasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
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.
There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels ofrifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutinand fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
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 .)
Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism throughCYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimuslevels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.(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. Thiseffect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. Ifshort-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, considerationshould be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19inhibitor. 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 theXELJANZ ®[tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C maxby 20-32% and increases t 1/2by 25-50% due to inhibition ofmetabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Oral Contraceptives
Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevanteffects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Although not studied in vitroor 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 andpimozide is contraindicated.
Although not studied in vitroor in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Useof quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine iscontraindicated. (See CONTRAINDICATIONS .)
In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increasedplasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjectsreceiving concomitant diuretics.
A study observed a reduction in clearance and distribution volume as well as prolongation of t 1/2 of alfentanil following concomitant treatment withfluconazole. A possible mechanism of action is fluconazoles inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline
Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combinationtherapy 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 smalladditive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism ofthe two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.
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 thepharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There wasno significant pharmacokinetic interaction between fluconazole and azithromycin.
Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developingcarbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.
Calcium Channel Blockers
Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has thepotential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.
During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C maxand AUC increased by 68% and 134%,respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.
Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may beused while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.
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. Elevatedfentanyl concentration may lead to respiratory depression.
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 throughCYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should beobserved for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should bediscontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.
Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonismwhich occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.
Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs
The C maxand AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration offlurbiprofen alone. Similarly, the C maxand 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 ofdosage of NSAIDs may be needed.
There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three monththerapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increasedmetabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortexinsufficiency when fluconazole is discontinued.
Fluconazole increases the AUC of saquinavir by approximately 50%, C maxby approximately 55%, and decreases clearance of saquinavir byapproximately 50% due to inhibition of saquinavirs hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavirmay be necessary.
Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. Thiscombination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids
Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, whichis possibly due to an inhibitory effect on CYP3A4.
Vitamin A
Based on a case report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNSrelated undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. Thiscombination may be used but the incidence of CNS related undesirable effects should be borne in mind.
Fluconazole increases C maxand 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 thiscombination 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 beenconducted, 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 hepatocellularadenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphomaL5178Y system. Cytogenetic studies in vivo(murine bone marrow cells, following oral administration of fluconazole) and in vitro(human lymphocytesexposed to fluconazole at 1000 mcg/mL) showed no evidence of chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of5, 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, and40 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 ofneonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced byhigh doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY .)
Teratogenic Effects
A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in uteroto high dose maternal fluconazole(400-800 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 usedduring pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy .)
Human Data
Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole inpregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defectsamong infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The featuresseen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones,arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies.
Animal Data
Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), andabortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed.
In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weightswere increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supemumerary ribs, renal pelvisdilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate andabnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects oflowered estrogen on pregnancy, organogenesis, and parturition.
Nursing mothers
Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when Fluconazole inSodium Chloride Injection, USP is administered to a nursing woman.
Pediatric use
An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to13 years of age. (See CLINICAL STUDIES .)
The use of fluconazole in children with cryptococcal meningitis, Candidaesophagitis, or systemic Candidainfections is supported by the efficacyshown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokineticstudies in children (see CLINICAL PHARMACOLOGY ) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION .)
In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of fluconazole wassimilar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baselinesymptoms (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 thesepatients relapsed at 10 and 18 days, respectively, following cessation of therapy.
The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study offluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment ofcryptococcal meningitis in children.
The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS .)
Efficacy of fluconazole has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY .) A small number of patients(29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.
Geriatric use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n=339) than foryounger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual sideeffects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similarproportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketingexperience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12and 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 ishowever 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 differentlyfrom younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and youngerpatients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function,care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION .)
Adverse reactions
Fluconazole in Sodium Chloride Injection, USP is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test resultsand hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationshipto treatment is uncertain.
In Patients Receiving Multiple Doses
Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinuedin 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 inHIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar inthe two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving fluconazole for 7 or moredays in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole. (See WARNINGS .) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasisand fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlyingmedical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, includinghepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline ondiscontinuation of fluconazole.
In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significantincrease 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. Theoverall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patientsin clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom werereceiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases wasgreater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oralsulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic:In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported.
Body as a Whole:Asthenia, fatigue, fever, malaise.
Cardiovascular:QT prolongation, torsade de pointes. (See PRECAUTIONS .)
Central Nervous System:Seizures, dizziness.
Hematopoietic and Lymphatic:Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.
Metabolic:Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses:Taste perversion.
Musculoskeletal System:Myalgia.
Nervous System:Insomnia, paresthesia, somnolence, tremor, vertigo.
Skin and Appendages:Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS ), alopecia.
Adverse Reactions in Children
The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazoleat doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonlyreported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due toadverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities wereelevations of transaminases or alkaline phosphatase.
|Percentage of Patients With Treatment-Related Side Effects
Comparative Agents
|With any side effect
|Abdominal pain
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A 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
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL AND INTRAVENOUSADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrationsclose to steady-state by the second day of therapy.
The daily dose of Fluconazole in Sodium Chloride Injection, USP for the treatment of infections should be based on the infecting organism and thepatients response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection hassubsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrentoropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis
The recommended dosage of Fluconazole in Sodium Chloride Injection, USP for oropharyngeal candidiasis is 200 mg on the first day, followed by 100mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2weeks to decrease the likelihood of relapse.
Esophageal candidiasis
The recommended dosage of Fluconazole in Sodium Chloride Injection, USP for esophageal candidiasis is 200 mg on the first day, followed by 100 mgonce daily. Doses up to 400 mg/day may be used, based on medical judgment of the patients response to therapy. Patients with esophageal candidiasisshould be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
Systemic Candidainfections
For systemic Candidainfections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapyhave 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 Candidaurinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of smallnumbers 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 400mg once daily may be used, based on medical judgment of the patients response to therapy. The recommended duration of treatment for initial therapyof cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of Fluconazole in SodiumChloride Injection, USP for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.
Prophylaxis in patients undergoing bone marrow transplantation
The recommended Fluconazole in Sodium Chloride Injection, USP daily dosage for the prevention of candidiasis in patients undergoing bone marrowtransplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should startFluconazole in Sodium Chloride Injection, USP prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after theneutrophil 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
|3 mg/kg
|100 mg
|6 mg/kg
|200 mg
|12* mg/kg
|400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY .) Based onthe prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive thesame dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. Noinformation regarding fluconazole pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis
The recommended dosage of Fluconazole in Sodium Chloride Injection, USP for oropharyngeal candidiasis in children is 6 mg/kg on the first day,followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis
For the treatment of esophageal candidiasis, the recommended dosage of Fluconazole in Sodium Chloride Injection, USP in children is 6 mg/kg on thefirst day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patients response to therapy.Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following the resolution of symptoms.
Systemic Candidainfections
For the treatment of candidemia and disseminated Candidainfections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative studyof 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 of12 mg/kg once daily may be used, based on medical judgment of the patients response to therapy. The recommended duration of treatment for initialtherapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcalmeningitis in children with AIDS, the recommended dose of Fluconazole in Sodium Chloride Injection, USP is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function
Fluconazole is cleared primarily by renal excretion as unchanged drug. In patients with impaired renal function who will receive multiple doses ofFluconazole in Sodium Chloride Injection, USP, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (accordingto 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 neededdepending 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 beused to estimate the creatinine clearance in adults:
|Weight (kg) x (140 - age)
|72 x serum creatinine (mg/100 mL)
|0.85 x above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renalinsufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children:
|K x
|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.)
Fluconazole in Sodium Chloride Injection, USP is administered by intravenous infusion. Fluconazole has been used safely for up to fourteen daysof intravenous therapy. The intravenous infusion of Fluconazole in Sodium Chloride Injection, USP should be administered at a maximum rate ofapproximately 200 mg/hour, given as a continuous infusion.
Fluconazole in Sodium Chloride Injection, USP in INTRAVIA plastic containers is 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 containerpermit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Intravenous Use of Fluconazole in Sodium Chloride Injection, USP in INTRAVIA 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 primarycontainer before administration of the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or notpresent, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilizationprocess 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.
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
Fluconazole in Sodium Chloride Injection, USP for intravenous infusion administration is formulated as sterile iso-osmotic solution containing 2 mg/mLof fluconazole. It is supplied in INTRAVIA plastic containers containing volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively.
Fluconazole in Sodium Chloride Injection, USP in INTRAVIA Plastic Containers:
|Fluconazole in Sodium Chloride Diluent
|200 mg/100 mL x 6
|Fluconazole in Sodium Chloride Diluent
|200 mg/100 mL x 10
|Fluconazole in Sodium Chloride Diluent
|400 mg/200 mL x 6
|Fluconazole in Sodium Chloride Diluent
|400 mg/200 mL x 10
|Fluconazole in Sodium Chloride Diluent (NOVAPLUS)
|200 mg/100 mL x 6
|Fluconazole in Sodium Chloride Diluent (NOVAPLUS)
|400 mg/200 mL x 6
Store between 77F (25C) and 41F (5C). Brief exposure up to 104F (40C) does not adversely affect the product. Protect from freezing. Avoidexcessive heat.
Rx only
- Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI Document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite1400, Wayne, PA, 19087-1898 USA, 2008.
- Clinical and Laboratory Standards Institute (CLSI). Methods for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI Document M44-A2, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400,Wayne, PA, 19087-1898 USA, 2009.
- Pfaller, M.A., Messer, S.A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R.J., and Diekemal, 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 LaboratoryStandard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70-75.
|Manufactured by:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For: Renaissance SSA, LLC
Newtown, PA 18940 USA
|Intravia is a registered trademark of Baxter International Inc.
Maalox is a registered trademark of Novartis AG.
NovaPlus is a registered trademark of Vizient, Inc.
Printed in the USA
Rev. March 2018
Ingredients and appearance - Product information
Fluconazole in sodium chloride injection- Fluconazole, sodium chloride
|Product Type
|Item Code (Source)
|Route of Administration
|Ingredient Name
|Fluconazole ( UNII: 8VZV102JFY)( Fluconazole - UNII: 8VZV102JFY )
|2 mgin 1 mL
|Ingredient Name
|Sodium chloride
|Marketing Category
|Application Number or Monograph Citation
|Territorial Authority
|Marketing Start Date
Fluconazole in sodium chloride injection- Fluconazole, sodium chloride
|Product Type
|Item Code (Source)
|Route of Administration
|Ingredient Name
|Fluconazole ( UNII: 8VZV102JFY)( Fluconazole - UNII: 8VZV102JFY )
|2 mgin 1 mL
|Ingredient Name
|Sodium chloride
|Marketing Category
|Application Number or Monograph Citation
|Territorial Authority
|Marketing Start Date
Labeler - Renaissance SSA, LLC( 079777043)
Principal display panel
100 mL
in Sodium Chloride Injection, USP
200 mg/ 100 mL (2 mg/mL)*
200 mg
Rx Only
Principal display panel
100 mL
in Sodium Chloride Injection, USP
200 mg/ 100 mL (2 mg/mL)*
200 mg
Rx Only
Principal display panel
200 mL
in Sodium Chloride Injection, USP
400 mg/ 200 mL (2 mg/mL)*
400 mg
Rx Only
Principal display panel
200 mL
in Sodium Chloride Injection, USP
400 mg/ 200 mL (2 mg/mL)*
400 mg
Rx Only
Principal display panel
100 mL
in Sodium Chloride Injection, USP
200 mg/ 100 mL (2 mg/mL)*
200 mg
Rx Only
Principal display panel
200 mL
in Sodium Chloride Injection, USP
400 mg/ 200 mL (2 mg/mL)*
400 mg
Rx Only


text:
Sustainable initiatives
Sustainable teaching, research and operations
With a wealth of natural and landscaped open space across a 166-hectare campus, almost anywhere you walk, you'll see why the surrounding West Coast campus inspires us—in our teaching, our research, and in how we plan and manage our campus.
The 2012 UVic Strategic Plan, A Vision for the Future: Building on Excellence, calls for the establishment of a formal framework to manage the university's physical and financial resources in a sustainable manner; that is, with attention paid to the "triple bottom line" of economic, social, and environmental consequences.
The sustainability site is the digital hub for sustainability on the University of Victoria campus. We invite you to explore our green initiatives on the ground, in the classroom, and in our research activities. Connect with student groups, learn tips to reduce your impact and find out how you can get involved.
Sustainability on campus
Sustainability is a key part of the curriculum in nearly every major field at UVic, from science and engineering to social sciences and law. The Gustavson Business School makes sustainability a core component of its curriculum as well, and is home to two research centres devoted to sustainable economies and business practices.
Across the board, UVic research is at the forefront of sustainability breakthroughs for our changing world. We're a global leader in climate and ocean sciences, and sustainable energy research as well. UVic was also selected to host and lead the Pacific Institute for Climate Solutions (PICS), a province-wide hub for internationally leading climate change research.
Our campus operations also reflect our focus on sustainability. All our new buildings are constructed to meet the LEED Gold standard, one of the highest green building ratings in the world. Most are situated on former parking lots to preserve our natural spaces.
Valuable initiatives across campus—from strategic purchasing changes and transportation initiatives, to student-led proposals and changes in teaching curriculum—have further embraced sustainability in ways that bring both tangible results and an increased level of cultural know-how that continues to help us improve, individually and institutionally.


text:
By Laura Koran
Talks will resume next week on the future of Iran's nuclear program with the goal of beginning to draft a comprehensive agreement in May, a senior Obama administration official said on Friday.
The next round of negotiations will seek to build on the work that has been done since January, when an interim deal between Iran and the five permanent members of the U.N. Security Council took effect.
That deal eased some economic sanctions in return for Iran rolling back parts of its nuclear program, which the United States and others believe is designed to produce a weapon. Iran says its nuclear intentions are peaceful.
While officials in Washington are optimistic that negotiations are progressing on track, a number of significant potential roadblocks need to be worked through if a long-term agreement is to be reached.FULL STORY
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Автотехцентр RMS существует все более и более двадцать полет. Грандиозный полученный опыт точно по ремонтным работам автотранспорта произвольных типов. Я изготавливаем уход какой-нибудь конструкции на толерантным тарифам.
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What a day disaster this deal was ! It's crazy to think this country is going to be nuclear one day . There ideology is completely whacked out !
This deal was a complete failure! Why did CNN stop updating this site! Anyway you can't trust the Iranians!
The youre very professional .
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With John Kerry policy, the Iran regime would have a nuclear bomb in Two months.
The criminal Al assad killed all the oppositions and stayed for ever as president and Al Maleki copied him to kill all sunni and give the control of Syria and Iraq and Lebanon under terrorist group of hezbulah and Iran regime.
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America is the root of all terror. America has invaded sixty countries since world war 2.
In 1953 America overthrow Iran's democratic government Mohammad Mosaddegh and installed a brutal dictator Shah. America helped Shah of Iran to establish secret police and killed thousands of Iranian people.
During Iran-Iraq war evil America supported Suddam Hossain and killed millions of Iranian people. In 1989, America, is the only country ever, shot down Iran's civilian air plane, killing 290 people.
In 2003,America invaded Iraq and killed 1,000,000+ innocent Iraqi people and 4,000,000+ Iraqi people were displaced.
Now America is a failed state with huge debt. Its debt will be 22 trillion by 2015.
Well put, john smith. Thanks a million.
Russia once accidentally shot down an South Korean airliner. The US is not the only country to ever make a mistake.


text:
Cubs' entire schedule to be broadcast in HD
MESA, Ariz. -- The Cubs announced their 2014 regular-season television broadcast schedule, and for the sixth straight season, all 162 games will be available in high definition in the Chicago area.
WGN will televise the Cubs' March 31 season opener at Pittsburgh at 12:05 p.m. CT, and Comcast SportsNet will broadcast the next game, April 2 in Pittsburgh at 6:05 p.m. on Comcast SportsNet Plus. WCIU will televise its first game on April 20, when the Cubs host the Reds at 1:20 p.m.
WGN will broadcast Wrigley Field's 100th anniversary game on April 23 against the D-backs.
Cubs games have been televised by WGN since 1948 and by WCIU since 2000. This will be Comcast SportsNet's 10th season televising the Cubs.
Len Kasper returns for his 10th season in the Cubs' television booth. and will be joined by analyst Jim Deshaies for his second season.


text:
This may not be quite the right forum to post this question, but since it's the only one pertaining directly to Ext JS 4, I thought it would be best.
I can't seem to find a "Getting Started Guide" for the 4.0 release. I'm sure this is due to the "Developer Preview", but I've never worked with Ext JS before, so any help would be appreciated.
Anybody have a "quickstart" guide for 4.0? I've heard that there is new a build process in place, and I want to make sure I start using it from the beginning.


text:
Know Before You Go: Guidance for travel in Great Britain and Northern Ireland
Life may have been on pause recently, but that doesn't mean you can't start dreaming of exploring our beautiful countryside, wandering our sandy shores and discovering our historic landmarks once more.
Our traditional pubs, stately homes and glorious gardens are reopening, ready to give you a warm British welcome once again. In the meantime, you can still delve into our heritage, revel in our culture, and dig into our foodie delights from afar. Check out our latest articles or hop on over to our social channels for more tips, trivia and travel inspiration – it's all you need to imagine a true taste of Britain.