Drug: Diflucan

DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. REFERENCES 1. 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, Suite 1400, Wayne, PA,19087-1898 USA, 2008

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DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. In Patients Receiving Multiple Doses for Other Infections Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during 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 DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects
  Fluconazole
(N=577) Comparative Agents
(N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 Read the Diflucan (fluconazole) Side Effects Center for a complete guide to possible side effectsLearn More »

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Dosage And Administration In Adults Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage And Administration In Children The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 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 DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose > 50 100% ≤ 50 (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: (weight in kg) x (140 – age) (72) x serum creatinine (mg/100 mL) Females (0.85) x (above value) Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K 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.) Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. Preparation for Administration:
  1. Suspend container from eyelet support.
  2. Remove plastic protector from outlet port at bottom of container.
  3. Attach administration set. Refer to complete directions accompanying set.

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(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN 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 of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Tofacitinib
Triazolam
Oral Contraceptives
Pimozide
Quinidine
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
Vitamin A
Zidovudine Oral hypoglycemic Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine DIFLUCAN significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies). This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration. Rifampin Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole 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. . Rifabutin There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Voriconazole Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tofacitinib Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Triazolam Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32%, and increases t½ by 25-50 % due to the inhibition of metabolism 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 relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. Pimozide Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Quinidine Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS.) Hydrochlorothiazide In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Alfentanil A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline Fluconazole increases the effect of amitriptyline and nortriptyline. 5nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Azithromycin An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Carbamazepine Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium Channel Blockers Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Halofantrine Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. HMG-CoA reductase inhibitors The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Losartan Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Prednisone There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Saquinavir Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Sirolimus Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Vinca Alkaloids Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A Based on a case report in one patient receiving combination therapy with all-transretinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Zidovudine Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Read the Diflucan Drug Interactions Center for a complete guide to possible interactions Learn More »

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DIFLUCAN (fluconazole) is indicated for the treatment of:
  1. Vaginal can didiasis (vaginal yeast infections due to Candida).
  2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candidaurinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.
  3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see Clinical Studies section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

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DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of 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.)Last reviewed on RxList: 4/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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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.

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DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30
NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30
NDC 0049-3430-41 Unit dose package of 100 Storage Store tablets below 86°F (30°C). DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle
NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. REFERENCES 3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. Distributed by: Roerig, Division of Pfizer Inc, NY, NY 10017. Revised March 2014 Last reviewed on RxList: 4/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Fluconazole should be administered with caution to patients with renal dysfunction. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and Clinical Studies.) Carcinogenesis, Mutagenesis, And Impairment Of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects Pregnancy Category C Single 150 mg tablet use for Vaginal Candidiasis There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. Pregnancy Category D All other indications A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to 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 used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (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 in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. 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, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing woman. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See Clinical Studies.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported ( > 1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) Last reviewed on RxList: 4/3/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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