Action And Clinical Pharmacology: Fluconazole is a highly selective inhibitor of fungal cytochrome P450 sterol C-14-a-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: 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 150 mg dose of fluconazole produced a mean Cmax of 2.70 g/mL (range: 1.91 to 3.70 g/mL).
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.
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.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.
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. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function.
Pharmacodynamics: The effects of fluconazole on the metabolism of carbohydrates, lipids, adrenal and gonadal hormones were assessed. In normal volunteers, fluconazole administration at 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 oral treatment of: vaginal candidiasis (yeast infections due to Candida).
The diagnosis of vaginal candidiasis should be confirmed by KOH smears and/or cultures before initiating therapy with fluconazole.
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: Anaphylaxis: In rare cases, anaphylaxis has been reported.
Hepatic injury: In the treatment of systemic infections multiple doses of 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.
Dermatologic: In rare cases, during the treatment of systemic infections, patients have developed exfoliative skin disorders during treatment with fluconazole.
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: General: The convenience of the single oral dose fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with fluconazole (26%) versus intravaginal agents (16%) in comparative clinical studies where no difference in efficacy was demonstrated (see Adverse Effects).
Fluconazole administered in combination with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases of up to 47% and 33% of ethinyl estradiol and levonorgestrel levels, respectively (see Precautions, Drug Interactions). The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment may be the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown.
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 should not be used in pregnant women unless the potential benefit outweighs the potential risk to the fetus.
Fluconazole was administered orally to pregnant rabbits during organogenesis in two 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 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 10 to 40 Â´ 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 for vaginal candidiasis 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 and Adolescents: The safety and effectiveness of fluconazole 150 mg capsules in the treatment of vaginal candidiasis in patients under 18 years of age have not been established.
Drug Interactions: Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed.
Oral Contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of fluconazole. The mean increase in ethinyl estradiol AUC was 6% (range: -47 to 108%) and levonorgestrel AUC increased 17% (range: -33 to 141%).
Twenty-five normal females received daily doses of both 200 mg fluconazole or placebo for two, 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 1 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).
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.
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 meanÂ±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 meanÂ±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 meanÂ±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 three 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 meanÂ±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 meanÂ±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 meanÂ±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; one 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.
Drug/Drug Interactions : Interaction studies with other medications have not been conducted, but such interactions may occur.
Drug/Laboratory Test Interactions : None known.
Adverse Reactions: In marketing experience with single dose fluconazole, rare cases of anaphylactic reaction and angioedema have been reported.
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: Vaginal Candidiasis: Oral: The recommended dosage for vaginal candidiasis is 150 mg as a single oral dose.
There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function.
Availability And Storage: Each hard white gelatin capsule, marked with Pfizer logo, contains: fluconazole 150 mg. Nonmedicinal ingredients: colloidal silicon dioxide, lactose, magnesium stearate, maize starch and sodium lauryl sulfate; capsule shell: gelatin and titanium dioxide. Unit dose blister (PVC) pack of 1. Store between 15 and 30°C.
DIFLUCAN-150 Pfizer Fluconazole Antifungal Agent