Biozole

Fluconazole.

BIOZOLE CAPSULE 150 mg: Each capsule contains Fluconazole 150 mg.
BIOZOLE CAPSULE 200 mg: Each capsule contains Fluconazole 200 mg.

Pharmacology: Pharmacodynamics: Fluconazole, a triazole antifungal agent, is a potent and specific inhibitor of fungal sterol synthesis. Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp, including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp; and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitidis, with Coccidioides immitis, including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals.
Pharmacokinetics: The pharmacokinetic properties of fluconazole are similar following IV or oral administration. After oral administration fluconazole is well absorbed, and systemic bioavailability exceeds 90% compared with intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations of the drug generally are attained within 1-2 hours with a terminal plasma elimination half-life of approximately 30 hours after administration. Plasma concentrations are proportional to dose. Administration of loading dose (on day 1) of twice the usual daily dose results in plasma levels close to steady-state by the second day. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).
Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. Fluconazole clearance is proportional to creatinine clearance.

Fluconazole is indicated for the treatment of the following conditions: Cryptococcosis: Including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts, and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
Systemic candidiasis: Including candidemia, disseminated candidiasis and other forms of invasive candidal infection including infections of the peritoneum, endocardium and pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors predisposing to candidal infection may be treated.
Mucosal candidiasis: These include oropharyngeal., oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.
Vaginal candidiasis: Acute or recurrent.
Prevention of fungal infection in patients with malignancy: Who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy.
Dermatomycosis: Including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and Candida infections.

The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Adults: For cryptococcal meningitis and cryptococcal infections at other sites: The usual dose is 400 mg on the first day followed by 200 mg once daily. Depending on the clinical response of the patient this dose may be increased to 400 mg daily. Usually, duration of treatment for cryptococcal meningitis is 6-8 weeks.
For the prevention of relapse of cryptococcal meningitis in patients with AIDS: After the patient receives a full course of primary therapy. Fluconazole may be administered indefinitely at a daily dose of at least 200 mg.
For candidemia, disseminated candidiasis and other invasive candidal infections: The usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response, the dose may be increased to 400 mg daily. Duration of treatment is upon the clinical response.
For oropharyngeal candidiasis: The usual dose is 50 mg once daily for 7-14 days. If necessary, treatment can be continued for longer periods in patients with severely compromised immune function.
For atrophic oral candidiasis associated with dentures: The usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
For other candidal infections of mucosa, (except vaginal candidiasis, see the following): E.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis, etc. the usual effective dose is 50 mg daily, given for 14-30 days. In unusually difficult cases of mucosal candidal infections, the dose may be increased to 100 mg daily.
For vaginal candidiasis: Fluconazole 150 mg should be administered as a single oral dose.
For the prevention of fungal infections in patients with malignancy: The dose should be 50 mg once daily while the patients is at risk as a consequence of receiving cytotoxic chemotherapy or radiotherapy.
For dermal infections: Including tinea pedis, tinea corporis, tinea cruris and Candida infections the recommended dosage is 150 mg once weekly or 50 mg once daily. Duration of treatment is normally 2-4 weeks but tinea pedis require treatment for up to 6 weeks. For tinea versicolor, the recommended dose is 50 mg once daily for 2-4 weeks.
The recommended fluconazole dosage for the prevention of candidiasis is 50 to 400 mg once daily, based on the patients risk for developing fungal infection while receiving cytotoxic chemotherapy or radiotherapy. For patients at high risk of systemic infection, e.g., patients who are anticipated to have profound or prolonged neutropenia, the recommended daily dose is 400 mg once daily. Fluconazole administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells per mm³.
For tinea unguium (onychomycosis): The recommended dosage is 150-450 mg once weekly for 3-12 months or treatment should be continued until infected nail is replaced (uninfected nail grown in).
Children: Although, as stated in the precautions section, use in children below the age of 16 is not recommended, where the treating physician considers. Fluconazole therapy imperative, the following doses are proposed: For children aged >1 year with normal renal function: The recommended daily dose is 1-2 mg/kg for superficial candidal infections, and 3-6 mg/kg for systemic candidal/cryptococcal infections.
For children with impaired renal function: The daily dose should be reduced in accordance with the guidelines given for adults, dependent on the degree of renal impairment.
Use in children 4 weeks of age and younger: Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hours. After the first two weeks, these children should be dosed once daily.
Use in Elderly: Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance <40 mL/min.) the dosage schedule should be adjusted as described in the following table.
Patients with renal impairment: Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single-dose therapy are necessary. In multiple-dose treatment of patients with renal impairment, normal doses should be given on days 1 and 2 of treatment and thereafter the dosage intervals should be modified in accordance with creatinine clearance as described in the following table. (See table.)

Click on icon to see table/diagram/image

In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

Fluconazole should not be used in patients with known sensitivity to the drug or to related azole compounds.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study.
Coadministration of cisapride is contraindicated in patients receiving fluconazole.

Very rarely, patients who died with severe underlying disease and who had received multiple-dose fluconazole had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic and/or had underlying diseases which could have caused the hepatic necrosis. Consequently, because a causal relationship with fluconazole cannot be excluded, in those patients in whom a significant rise of liver enzymes occurs, the risk-benefit ratio of continued fluconazole treatment should be assessed. In rare cases, as with other azoles, anaphylaxis has been reported.
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 patients 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.
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Azole antifungal, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram.
During post-marketing surveillance, there have been rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. Most reported cases involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant drugs that may have been contributed to these events. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.

Driving/Use of Machinery: Experience with fluconazole indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

There has been little use of fluconazole during pregnancy in humans. Adverse fetal effects have been seen in animals only at high-dose levels associated with maternal toxicity. These findings are not considered relevant to fluconazole used at therapeutic doses. However, use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.
Fluconazole is found 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 side effects associated with fluconazole are symptoms related to the gastrointestinal tract. These include nausea, abdominal pain, diarrhea and flatulence.
After gastro-intestinal symptoms, the second most commonly observed side effect was rash. 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 Warnings) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.
Patients with AIDS are more prone to the development of severe cutaneous reactions to many drugs. A small number of AIDS patients have developed such reaction, usually while receiving fluconazole concomitantly with other agents known to be associated with exfoliative cutaneous reactions. 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.
The most common undesirable effects observed with fluconazole are: Nervous System Disorders: Headache, dizziness, somnolence, seizures.
Hepatic Disorders: Hepatotoxicity including rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT, elevated SGPT, transient hepatic reactions, including hepatitis and jaundice. In addition, the following undesirable effects have occurred.
Hematologic/Lymphatic Disorders: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia.
Metabolic Disorders: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal Disorders: Nausea, abdominal pain, diarrhea, flatulence.
Dermatologic and Sensitivity Reaction Disorders: Rash, exfoliative skin disorders including Steven-Johnson Syndrome and toxic epidermal necrolysis, anaphylaxis, angioedema, pruritus, alopecia.

Warfarin: Fluconazole increased the prothrombin time after warfarin administration in healthy males. Though the magnitude of change was small (12%), careful monitoring of prothrombin time in patients receiving coumarin-type anticoagulants is recommended.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind.
Phenytoin: Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. A kinetic study in renal transplant patients found fluconazole 200 mg daily to slowly increase cyclosporin concentrations. However, in another multiple-dose study with 100 mg daily, fluconazole did not affect cyclosporin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Theophylline: In a placebo-controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. 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.
Azithromycin: Concomitant use of a single 1.2-g dose of azithromycin and a single 800-mg dose of fluconazole did not alter the pharmacokinetics of either drug.
Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. 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.
Cisapride: There have been reports of cardiac events including torsade de points 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.
Hydrochlorothiazide: In a kinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Oral Contraceptive: Three kinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 38% and 25%, respectively. In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
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.
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.
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. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg day of greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Zidovudine: In a study in men with HIV infections who received zidovudine (200 mg every 8 hours) alone or in conjunction with fluconazole (400 mg daily), the AUC of zidovudine was increased 74%, peak serum zidovudine concentrations were increased 84%, and the terminal elimination half-life of the drug was increased 128% in patients receiving concomitant fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
The use of fluconazole in patients concurrently taking astemizole of other metabolized by the cytochrome P-450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministration fluconazole.
Patients should be carefully monitored.
Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.

Store in a dry place at temperature not exceed 30°C.

Antifungals

J02AC01 - fluconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

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