Diflucan

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.

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%.

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

Benzodiazepines (Short Acting): Following oral or i.v. 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 i.v. If concomitant benzodiazepine therapy, such as midazolam or triazolam, is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.

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 C_max. There was a mean±SD decrease in fluconazole AUC of 13%±11% (range −3.4 to −31%) and C_max decreased 19%±14% (range: −5 to −40%). However, the administration of cimetidine 600 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.

Coumarin-Type Anticoagulants: In a clinical trial, 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.

During the postmarketing experience, as with some 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.

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.

Cyclosporine: Cyclosporine AUC and C_max 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, C_max, C_min (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean±SD increase in AUC was 92%±43% (range: 18 to 147%). The C_max increased 60%±48% range (range: −5 to 133%). The C_min increased 157%±96% (range: 33 to 360%). The apparent oral clearance decreased 45%±15% (range: −15 to −60%). 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.

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 (see Precautions—QT Prolongation). Patients should be carefully monitored.

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. 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. Coadministration of cisapride is contraindicated in patients receiving fluconazole (see Contraindications).

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.

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

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.

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 C_max following the administration of fluconazole. There was a mean±SD increase in tolbutamide AUC of 26%±9% (range: 12 to 39%). Tolbutamide C_max increased 11%±9% (range −6 to 27%).

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

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

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.

Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. 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.

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.

Tacrolimus: There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.

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, C_max, and half-life with a corresponding decrease in clearance. The mean±SD theophylline AUC increased 21%±16% (range: −5 to 48%). The C_max increased 13%±17% (range: −13 to 40%). Theophylline clearance decreased 16%±11% (range: −32 to 5%). The half-life of theophylline increased from 6.6±1.7 hours to 7.9±1.5 hours. 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.

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.

Drugs exhibiting no significant pharmacokinetic interactions with fluconazole: 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.

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

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.

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

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 1616 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.

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 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.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included 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 (see Precautions, Drug Interactions and Adverse Effects).

None known.

Each pink tablet, marked with “Pfizer” on one side and “Diflucan 50” on the other side, 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. Store at 15 to 30°C.

Each pink tablet, marked with “Pfizer” on one side and “Diflucan 100” on the other side, 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 at 15 to 30°C.

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 at 15 to 30°C. Do not freeze.

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 at 15 to 30°C. After reconstitution: The reconstituted suspension is stable for 14 days at 5 to 30°C. Protect from freezing. Shake well before each use. Discard unused portion after 2 weeks (14 days).

anorexia, constipation, dyspepsia, flatulence.

anemia.

seizures.

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 1616 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 abnormalities.

taste perversion.

pruritus.

hepatic failure, hepatitis.

anaphylaxis including angioedema, face edema, pruritus, and urticaria.

leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.

In rare cases, anaphylaxis has been reported.

In addition, the following adverse events have occurred under conditions where a causal association is uncertain (e.g., open trials, during postmarketing experience):

hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Sixteen percent of over 4000 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 4048 patients receiving fluconazole for 7 or more days in clinical trials:

insomnia, somnolence.

convulsions, dizziness, paresthesia, tremor, vertigo.

myalgia.

fatigue, malaise, asthenia, fever.

cholestasis, hepatocellular damage, jaundice.

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%).

dry mouth, increased sweating.

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

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

QT prolongation, torsade de pointes (see Precautions—QT Prolongation).

There have been reports of overdosage with fluconazole and in one case, a 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8200 mg of fluconazole. The patient was admitted to the hospital, and his condition resolved within 48 hours.

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.