Fluxar

Fluconazole.

Each mL contains: Fluconazole 2 mg.

Pharmacotherapeutic Group: Triazole derivatives. ATC Code: J02AC.
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 dermatitides; with Coccidioides immitis, including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals.
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.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 200 to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single of multiple doses of fluconazole 50 mg do not affect its metabolism.
Pharmacokinetics: Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4-5 with multiple once daily dosing.
Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. 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.
High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 μg/g and 7 days after cessation of treatment the concentration was still 5.8 μg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 μg/g and 7 days after the second dose was still 7.1 μg/g.
Concentration of fluconazole in nails after 4 months of 150 mg once-a-week-dosing was 4.05 μg/g in healthy and 1.8 μg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy.
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.
A study compared the saliva and plasma concentrations of a single fluconazole 100 mg dose administered in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.
Pharmacokinetics In Children: In children, the following pharmacokinetic data have been reported: See Table 1.

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In premature newborns (gestational age around 28 weeks), intravenous administration of 6 mg/kg was given every third day for a maximum of five doses while the premature newborns remained in the intensive care unit. The mean half-life (hour) was 74 (range 44-185) on day 1, which decreased with time to a mean of 53 (range 30-131) on day 7and 47 (range 27-68) on day 13.
The area under the curve (mcg.h/mL) was 271 (range 173-385) on day 1, which increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13.
The volume of distribution (mL/kg) was 1183 (range 1070-1470) on day 1, which increased with time to a mean of 1184 (range 510-2130) on day 7 and 1328 (range1040-1680) on day 13.
Pharmacokinetics In Elderly: A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg.h/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 mcg.h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Co-administration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min.kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of this subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-life - creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life - creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly.

Therapy may be instituted before the results of the cultures and other laboratory studies are known, however, once these results become available, anti-infective therapy should be adjusted accordingly.
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. These include infections of the peritoneum, endocardium, eye, 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, esophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune functions may be treated. Prevention of relapse of oropharyngeal candidiasis in patients with AIDS.
Genital candidiasis. Vaginal candidiasis, acute or recurrent; and prophylaxis to reduce the incidence of recurrent vaginal candidiasis (3 or more episodes a year). Candidal balanitis.
Prevention of fungal infections 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, tinea unguium (onychomycosis), and dermal candida infections.
Deep endemic mycoses in immunocompetent patients, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

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 often require maintenance therapy to prevent relapse.
Use in Adults: For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 to 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis. For 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 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 based upon the clinical response.
For oropharyngeal candidiasis, the usual dose is 50 to 100 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 genital candidiasis [see as follows] (e.g., esophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis, etc.) the usual effective dose is 50 to 100 mg daily, given for 14-30 days.
For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the patients receive a full course of primary therapy, fluconazole may be administered at a 150 mg once weekly dose.
For the treatment of vaginal candidiasis, fluconazole 150 mg should be administered as a single oral dose.
To reduce the incidence of recurrent vaginal candidiasis, a 150 mg once monthly dose may be used. The duration of therapy should be individualized, but ranges from 4-12 months. Some patients may require more frequent dosing.
For Candida balanitis, fluconazole 150 mg should be administrated as a single oral dose.
The recommended fluconazole dosage for the prevention of candidiasis is 50 to 400 mg once daily, based on the patient's risk for developing fungal infection. 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.
The dermal infections including tinea pedis, corporis, cruris and candida infections, the recommended dosage is 150 mg once weekly or 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks.
For tinea versicolor, the recommended dose is 300 mg once weekly for 2 weeks; a third weekly dose of 300 mg may be needed in some patients, whereas, in some patients, a single dose of 300 to 400 mg may be sufficient. An alternate dosing regimen is 50 mg once daily for 2 to 4 weeks.
For tinea unguium, the recommended dosage is 150 mg once weekly. Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally requires 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals, and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured.
For deep endemic mycoses, doses of 200 to 400 mg daily for up to 2 years may be required. The duration of therapy should be individualized but ranges from 11-24 months with coccidioidomycosis, 2-7 months with paracoccidioidomycosis, 1-16 months will sporotrichosis and 3-17 months for histoplasmosis.
Use in Children: As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children. Fluconazole is administered as a single dose each day.
The recommended dosage of fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.
For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6 to 12 mg/kg daily, depending on the severity of the disease.
For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 to 12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see Use In Adults previously). (For children with impaired renal functional, see Use In Renal Impairment as follows).
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. During weeks 3 and 4 of life, the same dose should be given every 48 hours.
Use In Elderly: Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance <50 mL/min) the dosage schedule should be adjusted as described as follows.
Use In Renal Impairment: Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single-dose therapy are necessary. In patients (including children) with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: See Table 2.

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Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.
Administration: Fluconazole may be administered or by intravenous infusion at a rate not exceeding 10 mL/minute.

There have been reports of overdose with fluconazole accompanied by hallucinations and paranoid behavior.
In the event of overdose, 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%.

Co-administration 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. Co-administration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine is contraindicated in patients receiving fluconazole (see Precautions and Interactions).

Fluconazole should be administered with caution to patients with liver dysfunction.
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 patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.
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 serious 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.
The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see Contraindications and Interactions).
In rare cases, as with other azoles, anaphylaxis has been reported.
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.
Fluconazole should be administered with caution to patients with renal dysfunction (see Dosage & Administration).
Fluconazole is a potent CYP2C9 and CYP2C19 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see Interactions).

Use in Pregnancy: Data from several hundred pregnant women treated with doses <200 mg/day of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the fetus.
There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Adverse fetal effects have been seen in animals only at high dose levels associated with maternal toxicity. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-80x the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These affects 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.
A few published case reports describe a distinctive and a rare pattern of birth defects among infants whose mother received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.
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.
Use in Lactation: 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.
In some patients, particularly those with serious underlying diseases such as 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.
The following undesirable effects have been observed and reported during treatment with fluconazole with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 3.)

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Pediatric Population: The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults.

Concomitant use of the following other medicinal product is contraindicated: Cisapride: There have been reports of cardiac events including Torsades de Pointes in patients to whom fluconazole and cisapride were co-administered. 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. Concomitant treatment with fluconazole and 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. 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 per day or 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 (see Contraindications). The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Co-administration of fluconazole and astemizole is contraindicated (see Contraindications).
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de points. Co-administration of fluconazole and pimozide is contraindicated (see Contraindications).
Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use if quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Co-administration of fluconazole and quinidine is contraindicated (see Contraindications).
Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT internal, torsades de pointes) and consequently sudden heart death. Co-administration of fluconazole and erythromycin is contraindicated (see Contraindications).

Incompatibilities: Fluconazole intravenous infusion is compatible with the following administration fluids.
Dextrose 20, Ringer's solution, Hartmann's solution, Potassium chloride in dextrose, Sodium bicarbonate 4.2%, Aminofusin, Normal saline.
Fluconazole may be infused through an existing line with one of the above listed fluids.
Although no specific incompatibilities have been noted, mixing with any other drug prior to infusion is not recommended.

Store at temperatures not exceeding 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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