Fluconazole-Vertex, 50 mg capsules 7 pcs

Fluconazole is an antifungal agent and has a highly specific action by inhibiting the activity of cytochrome P450-dependent fungal enzymes. It blocks transformation of lanosterol of fungal cells into membrane lipid – ergosterol; it increases cell membrane permeability, disrupts cell growth and replication.

Fluconazole, being highly selective for cytochrome P450 of fungi, practically does not inhibit these enzymes in humans (in comparison with itraconazole, clotrimazole, econazole and ketoconazole it inhibits cytochrome P450 dependent oxidation processes in human liver microsomes to a lesser extent). It does not have antiadrogenic activity.

< br> Active in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis against immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp; in endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).

Indications

Active ingredient

Composition

1 capsule contains

Active substance:

fluconazole 50 mg

Excipients:

Corn starch,

povidone (polyvinylpyrrolidone),

colloidal silicon dioxide (aerosil),

sodium lauryl sulfate,

calcium stearate,

lactose.

Capsules are hard gelatin:

for 50 mg dosage – gelatin,

titanium dioxide,

Azorubin dye,

Sunset yellow dye and for 150 mg dosage – gelatin, titanium dioxide.

How to take, the dosage

Intravenously, swallowed whole.

Adults and children over 15 years of age (with body weight over 50 kg) in cryptococcal meningitis and cryptococcal infections of other localizations are usually prescribed 400 mg (8 50 mg capsules) on the first day and then continue treatment at a dose of 200 mg (4 50 mg capsules) to 400 mg (8 50 mg capsules) once daily. Duration of treatment in cryptococcal infections depends on clinical efficacy confirmed by mycological study; in cryptococcal meningitis the course of treatment should be at least 6-8 weeks.

To prevent relapse of cryptococcal meningitis in AIDS patients, fluconazole is prescribed at a dose of 200 mg (4 capsules of 50 mg) daily for an extended period of time after completion of the full course of initial therapy.

In candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose is 400 mg (8 50 mg capsules) in the first day and then 200 mg (4 50 mg capsules) daily. If clinical efficacy is insufficient, the drug dose may be increased to 400 mg (8 50 mg capsules) per day. The duration of therapy depends on the clinical effectiveness.

In oropharyngeal candidiasis the preparation is usually prescribed in dose of 150 mg once daily; duration of therapy is 7-14 days. If necessary, in patients with pronounced immune impairment the treatment may be longer.

For prevention of relapses of oropharyngeal candidiasis in AIDS patients after completion of the complete course of initial therapy – 150 mg once a week.

In atrophic oral candidiasis associated with wearing dentures – 50 mg once a day for 14 days in combination with local antiseptic drugs for denture treatment.

In other localizations of candidiasis (except genital candidiasis), such as esophagitis, non-invasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, etc, Effective dose is usually 150 mg per day with treatment duration of 14-30 days.
In case of vaginal candidiasis, fluconazole is taken orally in a single dose of 150 mg. To reduce the recurrence rate of vaginal candidiasis, the drug may be used in a dose of 150 mg once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use.

For balanitis caused by Candida, fluconazole is given orally in a single dose of 150 mg daily.

For prevention of candidiasis, the recommended dose is 50-400 mg once daily depending on the degree of risk of fungal infection. If there is a high risk of generalized infection, for example, in patients with expected severe or long-lasting neutropenia, the recommended dose is 400 mg/day. Fluconazole is prescribed several days before the expected appearance of neutropenia; after an increase in neutrophil counts above 1,000/μL, treatment is continued for another 7 days.

In mycoses of the skin, including mycoses of the feet, smooth skin, inguinal area, and candidiasis of the skin, the recommended dose is 150 mg once a week or 50 mg once a day; the dosing regimen depends on the clinical and mycological effect. Duration of therapy in normal cases is 2-4 weeks, but in foot mycoses longer therapy (up to 6 weeks) may be required.

In pityriasis 300 mg (2 capsules of 150 mg) once a week for 2 weeks, some patients need a third dose of 300 mg a week, while in some cases a single dose of 300-400 mg is sufficient; an alternative regimen of treatment is 50 mg once a day for 2-4 weeks.

In onychomycosis the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (the uninfected nail grows back). It normally takes 3-6 months and 6-12 months, respectively, to re-grow nails on the fingers and feet.
In deep endemic mycoses, the drug may need to be used at a dose of 200 mg (4 capsules of 50 mg) to 400 mg (8 capsules of 50 mg) daily for up to 2 years. The duration of therapy is determined individually; it may be 11-24 months. for coccidioidomycosis; 2-17 months. for paracoccidioidomycosis; 1-16 months. for sporotrichosis and 3-17 months. for histoplasmosis.

In children, as well as in similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children the drug should not be used in a daily dose which would exceed that of adults, i.e. not more than 400 mg per day. The drug is used daily once a day.

In patients who are regularly on dialysis, one dose of the drug is used after each session of hemodialysis.

Interaction

Protrombin time increases (on average by 12%) when using fluconazole with warfarin. In this regard, it is recommended to carefully monitor the prothrombin time in patients receiving the drug in combination with coumarin anticoagulants.
The half-life of oral hypoglycemic agents – sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide) may increase if concomitantly taken with fluconazole.

Concomitant use of fluconazole and phenytoin may increase plasma phenytoin concentrations to clinically significant levels. Therefore, if co-administration of these drugs is necessary, phenytoin concentrations should be monitored with dose adjustments to maintain drug levels within the therapeutic interval.

Combination with rifampin decreases AUC by 25% and shortens plasma elimination half-life of fluconazole by 20%. Therefore, it is reasonable to increase fluconazole dose in patients receiving rifampicin concomitantly.

Increase of cyclosporine concentration is possible in concomitant use with fluconazole at a dose of 200 mg/day.

In case of concomitant use with theophylline the average clearance rate of theophylline from plasma may decrease.
Concomitant use of fluconazole and cisapride may significantly increase plasma concentrations of cisapride; there have been reports of adverse reactions in the heart, including ventricular fibrillation/torsades de points and prolongation of QT interval on ECG.

The concomitant use of azole antifungal agents and terfenadine may cause significant increases in plasma terfenadine levels: serious arrhythmias may occur as a result of QT interval prolongation.

Concomitant use of fluconazole and hydrochlorothiazide may increase fluconazole plasma concentrations by 40%.
There have been reports of interaction of fluconazole and rifabutin with increased serum levels of the latter. There have been cases of uveitis during concomitant use of fluconazole and rifabutin. Patients receiving rifabutan and fluconazole concomitantly should be closely monitored.

In patients receiving a combination of fluconazole and zidovudine there is an increase in concentration of zidovudine that is caused by a decrease in conversion of the latter to its main metabolite, therefore an increase in side effects of zidovudine should be expected.

Increases the concentration of midazolam, due to which the risk of psychomotor effects increases (more pronounced when using fluconazole orally than intravenously).

Increases the concentration of tacrolimus, due to which the risk of nephrotoxic effects increases.

Special Instructions

Treatment should be continued until clinical and hematological remission occurs. Premature discontinuation of treatment leads to relapses.
In rare cases the use of fluconazole has been accompanied by toxic liver changes, including fatalities, mainly in patients with serious comorbidities.

In the case of hepatotoxic effects associated with fluconazole, no clear dependence on the total daily dose, duration of therapy, sex, and age of the patient was noted. Hepatotoxic effects of fluconazole were usually reversible; their signs disappeared after discontinuation of therapy. If clinical signs of liver damage appear, which may be associated with fluconazole, the drug should be discontinued.

AIDS patients are more prone to develop severe skin reactions when using many drugs. In cases where patients with superficial fungal infections develop a rash and it is considered definitely related to fluconazole, the drug should be discontinued. If rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme appear. Caution should be exercised when concomitantly taking fluconazole with rifabutin or other drugs metabolized by the cytochrome P450 system.

When fluconazole is coadministered with oral hypoglycemic agents (chlorpropamide, glibenclamide, glipizide, tolbutamide) in diabetic patients the blood glucose level should be controlled (possibility of hypoglycemia). It is recommended to monitor the concentration of cyclosporine in the blood when concomitant use with fluconazole.

Patients who receive high doses of theophylline concomitantly with fluconazole, or who are likely to develop theophylline intoxication, should be monitored for early detection of symptoms of theophylline overdose.

Impact on driving and operating machinery

Impairment of driving and operating machinery associated with use of the drug is unlikely.

Features

Fluconazole is well absorbed after oral administration, its bioavailability is 90%.

The maximum concentration after oral administration on an empty stomach of 150 mg of the drug is 90% of the concentration in plasma when administered intravenously at a dose of 2.5-3.5 mg/l. Simultaneous intake of food has no effect on absorption of fluconazole taken orally. Time of maximum concentration after oral administration on an empty stomach of 150 mg of the preparation – 0.5-1.5 hours.

The concentration in plasma is in direct relation to the dose. A 90% level of equilibrium concentration is reached by 4-5 days of treatment with the drug (when taken once daily). A “shock” dose (on the first day), twice the usual daily dose, allows reaching a concentration level corresponding to 90% of the equilibrium concentration by the second day. The volume of distribution is close to the total body water content. Binding with blood plasma proteins is 11-12%.

Fluconazole penetrates well into all body fluids. The concentration of the active substance in breast milk, joint fluid, saliva, sputum and peritoneal fluid is similar to that in plasma. Constant values in vaginal secretion are reached 8 hours after oral administration and are maintained at this level for at least 24 hours.

Fluconazole penetrates cerebrospinal fluid (CSF) well, in fungal meningitis the concentration in CSF is about 80% of its level in plasma. In sweat fluid, epidermis and stratum corneum (selective accumulation) concentrations exceeding serum concentrations are achieved.

On day 7 after oral administration of 150 mg of fluconazole its concentration in the stratum corneum is 23.4 mcg/g, one week after the second dose – 7.1 mcg/g. The concentration of fluconazole in healthy nails after 4 months of use at a dose of 150 mg once a week is 4.05 µg/g and 1.8 µg/g in affected nails.

It is an inhibitor of CYP2C9 isoenzyme in the liver. No fluconazole metabolites were found in peripheral blood.
It is excreted mainly by the kidneys (80% – unchanged, 11% – as metabolites). Half-life of fluconazole is about 30 hours. Clearance of fluconazole is proportional to creatinine clearance.

Fluconazole concentration in plasma decreases by 50% after hemodialysis for 3 hours.

Contraindications

With caution:

hepatic and/or renal impairment, rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, simultaneous administration of terfenadine and fluconazole at a dose less than 400 mg/day, simultaneous administration of potentially hepatotoxic drugs, alcoholism, potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, simultaneous administration of drugs that cause ar

Side effects

Gastrointestinal system: decreased appetite, changes in taste, nausea, vomiting, abdominal pain, flatulence, diarrhea, rarely – liver function disorders (hyperbilirubinemia, increased alanine aminotransferase activity, aspartate aminotransferase activity, increased alkaline phosphatase activity, jaundice, hepatitis, hepatocellular necrosis).

Nervous system disorders: headache, dizziness, excessive fatigue, rarely – seizures.

Blood organs: rarely – leukopenia, thrombocytopenia (bleeding, petechiae), neutropenia, agranulocytosis.

Cardiovascular system: prolongation of Q-T interval, ventricular fibrillation/tripping.

Allergic reactions:

cutaneous rash, rarely – multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

Other:

rarely – renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Overdose

Symptoms:

Hallucinations, paranoid behavior.

Treatment symptomatic:

Gastric lavage, forced diuresis.

Hemodialysis for 3 h reduces Plasma concentrations by approximately 50%.

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