Each capsule contains 150mg of fluconazole.
Excipients/Inactive Ingredients: APO-FLUCONAZOLE-150 (fluconazole) Capsules, 150mg, contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose, microcrystalline cellulose, stearic acid. The capsule shell contains: gelatin, sodium lauryl sulfate, sodium metabisulfite, titanium dioxide, talc.
Therapeutic Classification: Antifungal Agent.
Pharmacology: Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14-alphademethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14-alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.
Fluconazole capsules are indicated 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 capsules.
Vaginal Candidiasis - Oral: The recommended dosage of fluconazole capsules 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.
Symptoms: There has been one reported case of overdosage with fluconazole. A 42- year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reported ingested 8200 mg of fluconazole. The patient was admitted to 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 three hour hemodialysis session decreases plasma levels by approximately 50%.
Mice and rats receiving very high doses of fluconazole, whether orally or intravenously, 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.
Fluconazole capsules are contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients, or to related azole compounds. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400mg or higher based upon results of a multiple dose interaction study.
Coadministration of cisapride is contraindicated in patients receiving fluconazole. (See PRECAUTIONS.)
Anaphylaxis: In rare cases, anaphylaxis has been reported.
Hepatic Injury: In the treatment of systemic infections multiple doses of fluconazole have 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 or symptoms consistent with liver disease develop that may be attributable to fluconazole.
Dermatologic: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.
Cisapride: There have been reports of cardiac events including torsades de pointes in patients receiving concomitant administration of fluconazole with cisapride. Coadministration of cisapride is therefore contraindicated in patients receiving fluconazole.
QT Interval Prolongation: 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 the torsades 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.
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 REACTIONS).
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 up to 47% and 33% of ethinyl estradiol and levonorgestrel levels, respectively (see 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.
Use in Women of Child-Bearing Potential: Since the teratologic effects of fluconazole in humans are unknown, women taking fluconazole for vaginal candidiasis should consider using adequate contraception (see USE IN PREGNANCY as follows).
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.
Use in 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 800mg/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. There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester. 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 9.4x 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 40x the maximum recommended human dose) embryo lethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal craniofacial 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.
Use in Lactation: Fluconazole is secreted in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
Use in Children and Adolescents: The safety and effectiveness of fluconazole 150mg capsules in the treatment of vaginal candidiasis in patients under 18 years of age have not been established.
Use in Women of Child-Bearing Potential: Since the teratologic effects of fluconazole in humans are unknown, women taking fluconazole for vaginal candidiasis should consider using adequate contraception (see USE IN PREGNANCY as follows).
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.
Use in 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 800mg/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. There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester. 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 9.4x 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 40x the maximum recommended human dose) embryo lethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal craniofacial 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.
Use in Nursing Mothers: Fluconazole is secreted in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
Fluconazole is generally well tolerated.
The most common undesirable effects observed during clinical trials and associated with fluconazole are:
Central and Peripheral Nervous System: Headache.
Skin/Appendages: Rash.
Gastrointestinal: Abdominal pain, diarrhea, flatulence and nausea. In some patients, particularly those with serious underlying diseases e.g., AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see Precautions) have been observed during treatment with fluconazole and comparative agents but the clinical significance and relationship to treatment is uncertain.
Liver/Biliary: Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase, bilirubin, SGOT and SGPT.
In addition, the following undesirable effects have occurred during post-marketing:
Cardiac Disorders: QT prolongation, torsade de pointes.
Central and Peripheral Nervous System: Dizziness and seizures.
Skin/Appendages: Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Gastrointestinal: Dyspepsia and vomiting.
Hematopoietic and Lymphatic: Leukopenia including neutropenia and agranulocytosis, and thrombocytopenia.
Body as a Whole: Anaphylaxis (including angioedema, face edema, pruritus and urticaria).
Liver/Biliary: Hepatic failure, hepatitis, hepatocellular necrosis and jaundice.
Metabolic/Nutritional: Hypercholesterolemia, hypertriglyceridemia and hypokalemia.
Other Senses: Taste perversion.
Patients with AIDS are more prone to the development of severe cutaneous reactions to many drugs. If a rash develops in a patient treated for a superficial fungal infection which is considered attributable to fluconazole, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. In rare cases, as with other azoles, anaphylaxis has been reported.
Clinically or potentially significant drug interactions between fluconazole and the following gents/classes have been observed.
Oral Contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 50mg 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 200mg fluconazole or placebo for two, ten-day periods. The treatment cycles were one 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 200mg 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 60mg b.i.d. for 15 days. Fluconazole 200mg 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 400mg and 800mg 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 400mg 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 400mg/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. Coadministration of cisapride is therefore contraindicated in patients receiving fluconazole.
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 concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately 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, 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 of 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 100mg 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 200mg did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.
Antacid: Administration of Maalox (20mL) to 14 normal male volunteers immediately prior to a single dose of fluconazole 100mg had no effect on the absorption or elimination of fluconazole.
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after that administration of fluconazole 200 mg daily for 14 days in 8 renal transplant patients who had 2 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- hours 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: -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 100mg 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.
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.
Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15mg) 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 placebocontrolled 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 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 (2.5mg 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 (5mg 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; 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 (200mg daily, orally for 3 days, followed by 250mg 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 600mg 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 of clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin.
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.
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 Interaction: Interaction studies with other medications have not been conducted, but such interactions may occur.
Drug/Laboratory Test Interactions: None known.
J02AC01 - fluconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.
Apo-Fluconazole cap 150 mg
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