Diflucan (Fluconazole)

DIFLUCAN™

Pfizer

Fluconazole

Antifungal Agent

Action And Clinical Pharmacology: Fluconazole is a highly selective inhibitor of fungal cytochrome P450 sterol C-14-alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14-a-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.

Fluconazole is a polar bis-triazole antifungal drug. Studies have shown that fluconazole exhibits specificity as an inhibitor of the fungal as opposed to mammalian cytochrome P450 mediated reactions, including those involved in steroid biosynthesis and drug metabolism. Many of the clinical advantages of fluconazole are a result of its unique pharmacokinetic properties.

Pharmacokinetics: Adults: Absorption: The pharmacokinetic properties of fluconazole are similar following administration by the i.v. or oral routes and do not appear to be affected by gastric pH. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with i.v. administration. Essentially all of the administered drug reaches systemic circulation; thus, there is no evidence of first-pass metabolism of the drug. In addition, no adjustment in dosage is necessary when changing from p.o. to i.v. or vice versa.

Peak plasma concentrations (Cmax) in fasted normal volunteers occur rapidly following oral administration, usually between 1 and 2 hours of dosing with a terminal plasma elimination half-life of approximately 30 hours (range 20 to 50 hours) after oral administration. The long plasma elimination half-life provides the basis for once daily dosing with fluconazole in the treatment of fungal infections.

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

In normal volunteers, oral bioavailability as measured by Cmax and AUC was not affected by food when fluconazole was administered as a single 50 mg capsule; however Tmax was doubled.

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose on the first day of treatment consisting of twice the usual daily dose results in plasma concentrations close to steady state by the second day.

Pharmacokinetics in Children: In children, the following pharmacokinetic data have been reported.

Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 mL/min/kg (17%).

In premature newborns (gestation age 26 to 29 weeks), the mean (% cv) clearance within 36 hours of birth was 0.180 (35%, n=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, n=9) mL/min/kg 6 days later and 0.333 (56%, n=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours 6 days later and 46.6 hours 12 days later.

The dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients.

Distribution: The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%) and is constant over the concentration range tested (0.1 to 10 mg/L). This degree of protein binding is not clinically meaningful. Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body tissues and fluids studied. In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. Whole blood concentrations of fluconazole indicated that the drug freely enters erythrocytes and maintains a concentration equivalent to that of plasma.

Metabolism and Excretion: Fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Following administration of radiolabeled fluconazole, greater than 90% of the radioactivity is excreted in the urine. Approximately 11% of the radioactivity in urine is due to metabolites. An additional 2% of the total radioactivity is excreted in feces.

The pharmacokinetics of fluconazole do not appear to be affected by age alone but are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function (see Dosage). A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

Pharmacodynamics: The effects of fluconazole on the metabolism of carbohydrates, lipids, adrenal and gonadal hormones were assessed. In normal volunteers, fluconazole administration (doses ranging from 200 to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. In addition, fluconazole appears to have no clinically significant effects on carbohydrate or lipid metabolism in man.

Indications And Clinical Uses: For the treatment of oropharyngeal and esophageal candidiasis. Fluconazole is also effective for the treatment of serious systemic candidal infections, including urinary tract infection, peritonitis and pneumonia.

Cryptococcal meningitis.

Prevention of the recurrence of cryptococcal meningitis in patients with acquired immunodeficiency syndrome (AIDS).

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.

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

Contra-Indications: In patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study (see Precautions).

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

Anaphylaxis: In rare cases, anaphylaxis has been reported.

Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with fluconazole. In patients with serious underlying diseases (predominantly AIDS and malignancy) those have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress.

Cisapride: There have been reports of cardiac events including torsades de pointes in patients receiving concomitant administration of fluconazole with cisapride. Patients should be carefully monitored if fluconazole is to be coadministered with cisapride (see Precautions).

Precautions: Pregnancy: There are no adequate and well-controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were treated with high dose (400 to 800 mg/day) fluconazole therapy for coccidioidomycosis (an unapproved indication). Exposure to fluconazole began during the first trimester in all cases and continued for 3 months or longer. Fluconazole is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus.

Fluconazole was administered orally to pregnant rabbits during organogenesis in 2 studies: at 5, 10 and 20 mg/kg, and at 5, 25 and 75 mg/kg respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at 75 mg/kg (approximately 9.4 ´ the maximum recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at the 25 mg/kg dose. 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 mg/kg to 320 mg/kg (approximately 10 to 40 ´ the maximum recommended human dose), 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.

Women of Childbearing Potential: Since the teratologic effects of fluconazole in humans are unknown, women taking fluconazole should consider using adequate contraception (see Pregnancy).

There have been reports of multiple congenital abnormalities in infants whose mothers were treated with high dose (400 to 800 mg/day) fluconazole therapy for coccidioidomycosis (an unapproved indication). Exposure to fluconazole began during the first trimester in all cases and continued for 3 months or longer. Since there are no adequate studies in pregnant women to assess the potential for fetal risk, fluconazole should not be used in pregnant women unless the potential benefit outweighs the potential risk to the fetus.

Lactation: Fluconazole is secreted in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

Children: An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age.

In a noncomparative study of children with serious systemic fungal infections, fluconazole was effective in the treatment of candidemia (10 of 11 patients cured) and disseminated candidiasis (5 of 6 patients cured or improved).

Fluconazole was effective for the suppression of cryptococcal meningitis and/or disseminated cryptococcal infection in a group of 6 children treated in a compassionate 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.

In addition, the use of fluconazole in children with cryptococcal meningitis, candida esophagitis or systemic candida infections is consistent with the approved use of fluconazole in similar indications for adults and, is supported by pharmacokinetic studies in children (see Pharmacology) establishing dose proportionality between children and adults (see Dosage).

The safety of fluconazole in children has been established 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 Effects).

Efficacy of fluconazole has not been established in infants less than 6 months of age. A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.

Geriatrics: Fluconazole was well tolerated by patients aged 65 years and over.

In a small number of elderly patients with bone marrow transplant (BMT) in which fluconazole was administered prophylactically there was a greater incidence of drug discontinuation due to adverse reactions (4.3%) than in younger patients (1.7%).

Superinfections: Development of resistance to fluconazole has not been studied; however, there have been reports of cases of superinfection with candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

As for other anti-infectives used prophylactically, prudent medical practice dictates that fluconazole be used judiciously in prophylaxis, in view of the theoretical risk of emergence of resistant strains.

Drug Interactions: Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed.

Cimetidine: Absorption of orally administered fluconazole does not appear to be affected by gastric pH. Fluconazole 100 mg was administered as a single oral dose alone and 2 hours after a single dose of cimetidine 400 mg to 6 healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC (area under the plasma concentration-time curve) and Cmax. There was a mean±SD decrease in fluconazole AUC of 13%±11% (range -3.4 to -31%) and Cmax decreased 19%±14% (range: -5 to -40%). However, the administration of cimetidine 600 to 900 mg i.v. over a 4-hour period (from 1 hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.

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

Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in 8 renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean±SD increase in AUC was 92%±43% (range: 18 to 147%). The Cmax increased 60%±48% range (range: -5 to 133%). The Cmin increased 157%±96% (range: 33 to 360%). The apparent oral clearance decreased 45%±15% (range: -15 to -60%). Fluconazole administered at 100 mg daily dose does not affect cyclosporine pharmacokinetic levels in patients with bone marrow transplants. Fluconazole may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine.

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

Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended.

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

Oral Hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in 3 placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of fluconazole 100 mg daily for 7 days. In these 3 studies, 22/46 (47.8%) of fluconazole-treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia.

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

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

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

Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; 1 fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.

Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days, followed by 250 mg i.v. for 1 dose) both with and without the administration of fluconazole (oral fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean±SD increase in phenytoin AUC was 88%±68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin.

Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended.

Rifampin: Administration of a single oral 200 mg dose of fluconazole after 15 days of rifampin administered as 600 mg daily in 8 healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean±SD reduction in fluconazole AUC of 23%±9% (range: -13 to -42%). Apparent oral clearance of fluconazole increased 32%±17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4±4.4 hours to 26.8±3.9 hours.

Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin.

Zidovudine: Plasma zidovudine concentrations were determined on 2 occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least 2 weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean±SD increase in AUC was 20%±32% (range: -27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6±3.6 to 5.7±2.2. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

Theophylline: The pharmacokinetics of theophylline were determined from a single i.v. dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean±SD theophylline AUC increased 21%±16% (range: -5 to 48%). The Cmax increased 13%±17% (range: -13 to 40%). Theophylline clearance decreased 16%±11% (range: -32 to 5%). The half-life of theophylline increased from 6.6±1.7 hours to 7.9±1.5 hours. Patients who are receiving high doses theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and therapy modified appropriately if signs of toxicity develop.

Oral Contraceptives: In pharmacodynamic studies, single and multiple 50 mg oral doses of fluconazole produced an overall mean increase in ethinyl estradiol or levonorgestrel pharmacokinetics in healthy women taking oral contraceptives. At 200 mg of fluconazole daily, the AUCs of ethinyl estradiol and levonorgestrel were increased, 40% and 24%, respectively.

Twenty-five normal females received daily doses of both 200 mg of fluconazole tablets or placebo for 2, 10-day periods. The treatment cycles were 1 month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo.

Drugs Prolonging the QTc Interval: The use of fluconazole in patients concurrently taking drugs metabolized by the Cytochrome P450 system may be associated with elevations in the serum levels of these drugs. In the absence of definitive information caution should be used when coadministering fluconazole and such agents. Patients should be carefully monitored.

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. In one study, 6 healthy volunteers received terfenadine 60 mg b.i.d. for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36%±36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. However, another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg/day or greater significantly increases plasma levels of terfenadine when taken concomitantly. Therefore the combined use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see Contraindications). Patients should be carefully monitored if they are being concurrently prescribed fluconazole at multiple doses lower than 400 mg/day with terfenadine.

Astemizole: Definitive interaction studies with fluconazole have not been conducted. The use of fluconazole may be associated with elevations in serum levels of astemizole. Caution should be used when coadministering fluconazole with astemizole. Patients should be carefully monitored.

Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. Therefore, caution should be used when coadministering fluconazole with cisapride. Patients should be carefully monitored (see Warnings).

Drug/Drug Interaction: Interaction studies with other medications have not been conducted, but such interactions may occur.

Drug/Laboratory Test Interactions : None known.

Adverse Reactions: Adults: Sixteen percent of over 4 000 patients treated with 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.

Adverse clinical events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%). However, the patterns of adverse events 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 2 groups (1.5%).

The 2 most serious adverse clinical events noted during clinical trials were exfoliative skin disorders and hepatic necrosis.

Because most of these patients had serious underlying disease (predominantly AIDS or malignancy) and were receiving multiple concomitant medications, including many known to be hepatotoxic or associated with exfoliative skin disorders, the causal association of these reactions with fluconazole is uncertain. Two cases of hepatic necrosis and one exfoliative skin disorder (Stevens-Johnson syndrome) were associated with a fatal outcome (see Warnings).

The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4 048 patients receiving fluconazole 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%.

Other treatment-related clinical adverse events which occurred less commonly (0.2 to
Skin and Appendages: pruritus.

Musculoskeletal: myalgia.

Central and Peripheral Nervous System: convulsions, dizziness, paresthesia, tremor, vertigo.

Autonomic Nervous System: dry mouth, increased sweating.

Psychiatric: insomnia, somnolence.

Gastrointestinal: anorexia, constipation, dyspepsia, flatulence.

Liver and Biliary System: cholestasis, hepatocellular damage, jaundice.

Special Senses: taste perversion.

Hematopoietic: anemia.

General: fatigue, malaise, asthenia, fever.

Immunologic: In rare cases, anaphylaxis has been reported.

The following adverse experiences occurred under conditions (e.g., open trials marketing experience) where a causal association is uncertain:

CNS: seizures.

Dermatologic: exfoliative skin disorders including Stevens-Johnson Syndrome and toxic epidermal necrolysis (see Warnings), alopecia.

Hematopoietic and Lymphatic: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

Metabolic: hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Laboratory Test Abnormalities: Liver Function: Clinically significant increases were observed in the following proportions of patients: AST 1%, ALT 1.2%, alkaline phosphatase 1.2%, total bilirubin 0.3%. The incidence of elevated serum transaminases was independent of age or route (oral or i.v) of administration but was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid or oral hypoglycemic agents. Clinically significant increases also were more frequent in patients who: 1) had AST or ALT elevations greater than 3 times the upper limit of normal (>3´ULN) at the time of entering the study (baseline), 2) had a diagnosis of hepatitis at any time during the study and, 3) were identified as alcohol abusers. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in patients treated with fluconazole during clinical trials.

Renal Function: Clinically significant increases were observed in the following proportions of patients: BUN (0.4%) and creatinine (0.3%).

Hematological Function: Clinically meaningful deviations from baseline in hematologic values which were possibly related to fluconazole were observed in the following proportions of patients: hemoglobin (0.5%), white blood cell count (0.5%) and total platelet count (0.6%).

Children: In Phase II/III clinical trials conducted in the U.S. and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses ranging 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 (5.4%), abdominal pain (2.8%), nausea (2.3%) and diarrhea (2.1%). Treatment was discontinued in 2.6% of patients due to adverse clinical events and in 1% of patients due to laboratory test abnormality.

Symptoms And Treatment Of Overdose: Symptoms: There has been 1 reported case of overdosage with fluconazole. A 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8 200 mg of fluconazole. The patient was admitted to the hospital, and his condition resolved within 48 hours.

Treatment: In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in urine. A 3-hour hemodialysis session decreases plasma levels by approximately 50%.

Mice and rats receiving very high doses of fluconazole, whether orally or i.v., displayed a variety of nonspecific, agonal signs such as decreased activity, ataxia, shallow respiration, ptosis, lacrimation, salivation, urinary incontinence and cyanosis. Death was sometimes preceded by clonic convulsions.

Dosage And Administration: Oral (Tablets and Oral Suspension) and I.V. Treatment: Fluconazole is well absorbed and excreted predominantly unchanged in urine following oral administration in man. The oral bioavailability is essentially complete (greater than 90%), and is independent of dose. Peak plasma concentrations after oral administration are attained rapidly, usually within 2 hours of dosing. Since oral absorption is rapid and almost complete, the daily dose of fluconazole is the same for oral tablets and suspension and i.v. administration. The terminal plasma elimination half-life is approximately 30 hours (range 20 to 50 hours).

The daily dose of fluconazole and the route of administration should be based on the infecting organism, the patient’s condition and the response to therapy. Treatment should be continued until clinical parameters and laboratory tests indicate that an active fungal infection has been cured or 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.

Recommended Dosages in Adults and Children (see also Pharmacology): Loading Dose: Adults and children: Administration of a loading dose on the first day of treatment, consisting of twice the usual daily dose, results in plasma concentrations close to steady state by the second day. Patients with acute infections should be given a loading dose equal to twice the daily dose, not to exceed a maximum single dose of 400 mg in adults or 12 mg/kg in children, on the first day of treatment.

Oropharyngeal Candidiasis: Adults: 100 mg once daily. Treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

Children: 3 mg/kg once daily. Treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

Esophageal Candidiasis: Adults: 100 to 200 mg once daily. Patients should be treated for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms.

Children: 3 mg/kg to 6 mg/kg once daily. Patients should be treated for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms.

Systemic Candidiasis: (Candidemia and Disseminated Candidal Infections) Adults: 200 to 400 mg once daily. These patients should be treated for a minimum of 4 weeks and for at least 2 weeks following resolution of symptoms.

Children: 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of patients.

Cryptococcal Meningitis: Adults: 200 to 400 mg once daily. Although the duration of therapy for cryptococcal meningitis is unknown, it is recommended that the initial therapy should last a minimum of 10 weeks.

Children: 6 to 12 mg/kg once daily. The recommended duration for initial therapy is 10 to 12 weeks after the cerebrospinal fluid becomes culture-negative.

Prevention of Recurrence of Cryptococcal Meningitis in Patients with AIDS: Adults: 200 mg once daily.

Children: 6 mg/kg once daily.

Premature Neonates: Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns (see Pharmacology). Based upon the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children in the first 2 weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first 2 weeks, these children should be dosed once daily.

Neonates: No information regarding fluconazole pharmacokinetics in full-term newborns is available.

Prophylaxis in Adult Patients: The recommended fluconazole daily dosage for the prevention of candidiasis in adult patients undergoing bone marrow transplantation is 400 mg once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils/mm should start fluconazole prophylaxis several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1 000 cells/mm

Fluconazole may be administered either orally or by i.v. infusion. The i.v. infusion of fluconazole should be administered at a maximum rate of approximately 200 mg/hour given as a continuous infusion (see Directions for Use).

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:

Males: weight (kg) x (140-age) -72 x serum creatinine (mg/100 mL)

Females: 0.85 x the above value

Children: 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:

linear length or height K X – serum or creatine (mg/100mL)

Directions for Use: Mixing Directions: Powder for Oral Suspension: Prepare a suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Add 24 mL of water and shake vigorously to suspend powder and produce 35 mL suspension. Each 5 mL contains 50 mg fluconazole.

Directions for Use: I.V. Infusion: Inspect visually for particulate matter or discoloration prior to administration. Do not use if cloudiness or precipitation is evident.

Reject the contents as unsterile if the metal seal is broken. Not intended for multidose use: discard any portion not used when the seal is first broken.

Connect an i.v. giving set to the bottle of fluconazole i.v. solution and also insert a venting set through the bung. Infuse the i.v. solution at a maximum rate of 200 mg/hour. Flush fluconazole i.v. solution remaining in the giving set with sterile normal saline. Because fluconazole is available as a dilute saline solution, consideration should be given to the rate of fluid administration in patients requiring sodium or fluid restriction.

Incompatibility: It is recommended that fluconazole i.v. be infused separately.

Compatibility: Administration Sets (Giving Sets): The i.v. infusion is compatible with (i.e., not susceptible to absorption) sets constructed of a delivery tube (PVC) luer lock (modified phenylene oxide), flash ball (latex) drip chamber (polypropylene) and piercing spike (polypropylene).

Availability And Storage: I.V.: Each mL of sterile aqueous solution for direct infusion contains: fluconazole 2 mg and sodium chloride 9 mg. Clear glass bottles of 100 mL (2´100 mL), affording doses of 200 mg fluconazole, sealed with a rubber bung. Store below 30°C. Do not freeze.

Powder for Oral Suspension: On reconstitution with water (24 mL) each mL of the orange-flavored suspension contains: fluconazole 10 mg (i.e., equivalent to fluconazole 50 mg/5 mL). Nonmedicinal ingredients: citric acid, colloidal silicon dioxide, natural orange flavor, sodium benzoate, sodium citrate, sucrose, titanium dioxide and xanthan gum. Bottles of 350 mg in HDPE bottles of 35 mL.

Before reconstitution (i.e., dry powder): Store below 30°C. After reconstitution: The reconstituted suspension is stable for 14 days at room temperature between 5 and 30°C. Protect from freezing. Shake well before each use. Discard unused portion after 2 weeks (14 days).

Tablets: 50 mg: Each pink tablet contains: fluconazole 50 mg. Nonmedicinal ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, FD&C Red No. 40 aluminum lake dye, magnesium stearate, microcrystalline cellulose and povidone. Opaque polyethylene bottles of 50 and 100. Store below 30°C.

100 mg: Each pink tablet contains: fluconazole 100 mg. Nonmedicinal ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, FD&C Red No. 40 aluminum lake dye, magnesium stearate, microcrystalline cellulose and povidone. Opaque polyethylene bottles of 50 and 100. Store below 30°C.

DIFLUCAN™ Pfizer Fluconazole Antifungal Agent

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