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. Fluconazole is designated chemically as 2,4-difluoro-α,α 1 -bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C 13 H 12 F 2 N 6 O 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 mg, 100 mg, 150 mg, 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. Chemical Structure

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

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 to 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 to 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 cells/mm 3 ) 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/mm 3 . Dosage and Administration in Pediatric Patients Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in pediatric patients 6 months and older 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 pediatric patients 6 months and older 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: The following dosing regimens in Table 6 are recommended for pediatric patients to achieve systemic exposures similar to adults for the treatment of systemic Candida infections, i.e., to maintain an AUC 0-24 between 400-800 mg*h/L. Table 6: Recommended Dosing Regimens for the Treatment of Systemic Candida Infections in Pediatric Patients Patient age Dosing regimen 3 months and older A loading dose of 25-mg/kg on the first day (not to exceed 800 mg) followed by 12-mg/kg once daily (not to exceed 400 mg). Birth to 3 months postnatal age and gestational age 30 weeks and above 25-mg/kg on the first day, followed by 12-mg/kg once daily Birth to 3 months postnatal age and gestational age less than 30 weeks 25-mg/kg on the first day, followed by 9-mg/kg once daily Patients with systemic candidiasis should be treated for a minimum of 3 weeks and for at least 2 weeks following the resolution of symptoms. Dosing in Pediatric Patients on ECMO: The recommended dosage of DIFLUCAN in pediatric patients 3 months and older on ECMO is 35-mg/kg on the first day (not to exceed 800 mg) followed by 12-mg/kg once daily (not to exceed 400 mg). For patients from birth to 3 months postnatal age, and gestational age less than 30 weeks, a loading dose of 35-mg/kg on the first day followed by 9-mg/kg once daily is recommended. For patients from birth to 3 months postnatal age and gestational age 30 weeks and above, a loading dose of 35-mg/kg on the first day followed by 12-mg/kg once daily is recommended. 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 to 12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in pediatric patients 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 mg to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following summary: Creatinine Clearance (mL/min) Recommended Dose (%) >50 100 ≤50 (no dialysis) 50 Hemodialysis 100% after each hemodialysis Patients on hemodialysis should receive 100% of the recommended dose after each hemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in pediatric patients with renal insufficiency, dosage reduction in pediatric patients with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in pediatric patients: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for pediatric patients older than 1 year and 0.45 for infants.) Administration DIFLUCAN is administered orally. DIFLUCAN can be taken with or without food. 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 30°C (86°F) and 5°C (41°F) and discard unused portion after 2 weeks. Protect from freezing.

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 other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS .)

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%. Hepato-biliary: 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 including fixed drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (See WARNINGS ), alopecia. Adverse Reactions in Pediatric Patients: 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 pediatric patients 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 Clinical Trials Experience in Pediatric Patients Safety in Prophylaxis of Invasive Candida Infections in Premature infants weighing less than 750 grams at birth In a Phase 3 clinical trial of pediatric patients (premature infants weighing less than 750 grams at birth), the incidence of intestinal perforation in infants receiving DIFLUCAN prophylaxis was higher compared to infants receiving placebo (see PRECAUTIONS: Pediatric Use ). Safety in Pediatric Patients Receiving ECMO A cohort of 20 pediatric patients (1 day to 17 years of age) on ECMO received DIFLUCAN in a prospective, open-label, single-center safety and PK ECMO study. The adverse reaction profile of DIFLUCAN in these patients was similar to that of adult and pediatric non-ECMO patients (See PRECAUTIONS: Pediatric Use ).

(See CONTRAINDICATIONS .) Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with DIFLUCAN, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed and are described in greater detail below: Abrocitinib: Drug interaction studies indicate that when coadministered with fluconazole (strong inhibitor of CYP2C19; moderate inhibitor of CYP2C9 and CYP3A4), the systemic exposure of abrocitinib and its active metabolites increased (See CLINICAL PHARMACOLOGY ). Avoid concomitant use of abrocitinib with DIFLUCAN. Refer to the abrocitinib Prescribing Information for additional details. Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of t ½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg). Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1 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 Candida 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. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. 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 . ) Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Cyclosporine: 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. 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. 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 (decreased hepatic metabolism of the statin). 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. Dose reduction of statins may be needed. Refer to the statin-specific prescribing information for details. 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. Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib. If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib. Ivacaftor and fixed dose ivacaftor combinations (e.g., tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor): Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold. If used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole, a reduction in the dose of ivacaftor (or ivacaftor combination) is recommended as instructed in the ivacaftor (or ivacaftor combination) prescribing information. Lemborexant: Concomitant administration of fluconazole increased lemborexant Cmax and AUC by approximately 1.6- and 4.2-fold, respectively which is expected to increase risk of adverse reactions, such as somnolence. Avoid concomitant use of DIFLUCAN with lemborexant. 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. Lurasidone: Concomitant use of moderate inhibitors of CYP3A4 such as fluconazole may increase lurasidone plasma concentrations. If concomitant use cannot be avoided, reduce the dose of lurasidone as instructed in the lurasidone prescribing information. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other non-steroidal anti-inflammatory drugs (NSAIDs) that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Olaparib: Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of olaparib as instructed in the LYNPARZA ® (Olaparib) Prescribing Information. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple-dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of 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 .) 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 .) Pimozide: Although not studied in vitro or in vivo , concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a 3 month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Quinidine: Although not studied in vitro or in vivo , concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS . ) Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Rifampin: Rifampin enhances the metabolism of concurrently administered 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 .) Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, C max by approximately 55%, and decreases the clearance of saquinavir by approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Short-acting benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) 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 .) Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies . ) Tolvaptan: Plasma exposure to tolvaptan is significantly increased (200% in AUC; 80% in C max ) when tolvaptan, a CYP3A4 substrate, is coadministered with fluconazole, a moderate CYP3A4 inhibitor. This interaction may result in the risk of a significant increase in adverse reactions associated with tolvaptan , particularly significant diuresis, dehydration, and acute renal failure. If tolvaptan and fluconazole are concomitantly administered, the tolvaptan dose should be reduced as instructed in the tolvaptan prescribing information and the patient should be frequently monitored for any adverse reactions associated with tolvaptan. Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C max by 20% to 32%, and increases t½ by 25% to 50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, central nervous system (CNS) related undesirable effects have developed in the form of pseudotumor cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies . ) Zidovudine: Fluconazole increases the C max and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.

Storage Store tablets below 30°C (86°F). 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 30°C (86°F). Store reconstituted suspension between 30°C (86°F) and 5°C (41°F) and discard unused portion after 2 weeks. Protect from freezing.