Flucostat, 150 mg capsules 2 pcs

Pharmacodynamics:

Fluconazole, a member of the triazole antifungal class, is a selective inhibitor of sterol synthesis in the fungal cell.

Fluconazole has demonstrated activity in-vitro and in clinical studies against most of the following microorganisms: Candidaalbicans, Candidaglabrata (many strains are moderately sensitive), Candidaparapsilosis, Candidatropicalis, Cryptococcusneoformans.

The activity of fluconazole against the following microorganisms has been shown, but its clinical significance is not known: Candidadubliniensis, Candidaguilliermondii, Candidakefyr, Candidalusitaniae.

In oral administration, fluconazole shows activity in various models of fungal infections in animals. It has demonstrated activity against opportunistic mycoses including those caused by Candidaspp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporumspp. and Trychophytonspp.

Fluconazole has high specificity against cytochrome P450-dependent fungal enzymes. Fluconazole therapy at a dose of 50 mg/day for up to 28 days has no effect on plasma testosterone concentrations in men or steroid concentrations in women of childbearing age.

Fluconazole at a dose of 200 to 400 mg/day has no clinically significant effect on endogenous steroid levels and their response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Mechanisms for the development of resistance to fluconazole

Resistance to fluconazole can develop in the following cases: a qualitative and quantitative change in the enzyme that targets fluconazole (lanosterol 14-α-demethylase), a decrease in access to the fluconazole target, or a combination of these mechanisms.

Point mutations in the ERG11 gene, which encodes the target enzyme, lead to target alteration and decreased affinity for azoles. Increased expression of the ERG11 gene leads to production of high concentrations of the target enzyme, which creates a need for increased fluconazole concentrations in the intracellular fluid to inhibit all enzyme molecules in the cell.

The second significant mechanism of resistance is the active excretion of fluconazole from the intracellular space through the activation of two types of transporters involved in the active excretion (efflux) of the drugs from the fungal cell.

These transporters include a major mediator encoded by the MDR (multidrug resistance) genes and an ATP-binding cassette transporter superfamily encoded by the CDR genes (Candida fungi resistance genes to azolovymantimycotics).

Hyperexpression of the MDR gene leads to resistance to fluconazole, while hyperexpression of CDR genes can lead to resistance to various azoles.

Resistance to Candidaglabrata is usually mediated by CDR gene overexpression, which leads to resistance to many azoles. For those strains in which the minimum inhibitory concentration (MIC) is defined as intermediate (16-32 µg/ml), maximum doses of fluconazole are recommended.

Candidacrosis should be considered resistant to fluconazole. The mechanism of resistance is associated with reduced sensitivity of the target enzyme to the inhibitory effects of fluconazole.

Pharmacokinetics:

Fluconazole pharmacokinetics are similar with intravenous and oral administration. After oral administration fluconazole is well absorbed, its plasma concentrations (and overall bioavailability) exceed 90% of those of intravenous administration.

Contemporaneous intake of food does not affect absorption of the drug taken orally. The plasma concentration is proportional to the dose and reaches a maximum (C_max) in 0.5-1.5 hours after fluconazole is taken on an empty stomach, and the elimination half-life is about 30 hours.

The maximum concentration of fluconazole in saliva when taking the capsule is reached after 4 hours.

The volume of distribution is close to the total water content in the body. Binding to plasma proteins is low (11-12%).

Fluconazole penetrates well into all body fluids. Concentrations of the drug in saliva and sputum are similar to its levels in blood plasma.

In the stratum corneum, epidermis, dermis and sweat fluids, high concentrations are achieved that exceed serum levels.

Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg once daily, fluconazole concentrations are 73 µg/g after 12 days and only 5.8 µg/g after 7 days of discontinuation of treatment. When used in a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on day 7 is 23.4 µg/g, and 7 days after the second dose is 7.1 µg/g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 in healthy nails and 1.8 µg/g in affected nails; 6 months after completion of therapy, fluconazole is still detectable in the nails.

Fluconazole is mainly excreted by the kidneys; approximately 80% of the administered dose is excreted unchanged. Fluconazole clearance is proportional to creatinine clearance. No fluconazole metabolites were detected in peripheral blood.

The long plasma elimination half-life allows fluconazole to be taken once for vaginal candidiasis.

Pharmacokinetics in elderly patients

It was found that with a single oral dose of fluconazole 50 mg in elderly patients aged 65 years and older, some of whom were also taking diuretics, C_max was reached 1.3 h after administration and was 1.54 µg/mL, the mean AUC (area under the concentration-time curve) was 76.4 ± 20.3 µg×h/mL, and the mean half-life was 46.2 h.

The values of these pharmacokinetic parameters are higher than in younger patients, which is probably due to the reduced renal function characteristic of older age. Concomitant administration of diuretics did not cause marked changes in AUC and C_max.

Creatinine clearance (74 ml/min), the percentage of fluconazole excreted unchanged by the kidneys (0-24 h, 22%) and the renal clearance of fluconazole (0.124 ml/min/kg) are lower in elderly patients compared to younger patients.

Indications

Active ingredient

Composition

Active ingredient:

fluconazole 50 mg or 150 mg;

excipients: lactose (milk sugar) 49.40 mg or 147.40 mg, corn starch 16.40 mg or 49.00 mg, colloidal silica (aerosil) 0.12 mg or 0.36 mg, magnesium stearate 0.96 mg or 2.88 mg, sodium lauryl sulfate 0.12 mg or 0.36 mg;

Solid gelatin capsules:

(for 50 mg dosage) body: titanium dioxide (E 171) – 3.0000%, iron oxide red (E 172) – 0.0857%, gelatin – up to 100%; lid: titanium dioxide (E 171) – 2.0000 %, iron oxide red (E 172) – 0.7286 %, gelatin – up to 100 %;

(for 150 mg dosage) case and cap: titanium dioxide (E 171) – 2.0000 %, gelatin – up to 100 %.

How to take, the dosage

Ingestion. The capsules are swallowed whole.

In acute vaginal candidiasis the drug is used once orally in a dose of 150 mg.

Use in the elderly

In elderly patients in the absence of renal dysfunction, the usual dosing regimen of the drug should be followed.

Use in patients with renal impairment

There is no need to change the dose on a single dose.

Interaction

Single or multiple administration of fluconazole in a dose of 50 mg does not affect the metabolism of fenazone (Antipyrine) when they are taken alone.

The simultaneous use of fluconazole with the following drugs is contraindicated:

Cisapride. Concomitant use of fluconazole and cisapride may cause adverse cardiac reactions, including torsadedepointes ventricular tachysystolic arrhythmia. Fluconazole administration in dose 200 mg once daily and cisapride in dose 20 mg four times daily causes significant increase of plasma concentration of cisapride and QT interval prolongation on ECG.

The concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine. Concomitant use of azole antifungal agents and terfenadine may cause serious arrhythmias due to prolongation of the QT interval. When fluconazole was administered at a dose of 200 mg/day it was not established an increase in the QT interval.

Special Instructions

When using fluconazole 150 mg for vaginal candidiasis, patients should be warned that improvement in symptoms is usually seen after 24 hours, but it sometimes takes several days for symptoms to disappear completely. If symptoms persist for several days, a doctor should be consulted.

In rare cases, the use of fluconazole has been accompanied by toxic liver changes, including fatalities, mainly in patients with severe 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; signs of them disappeared after discontinuation of therapy.

Patients who have liver function abnormalities during treatment with the drug should be monitored to detect signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole use, the drug should be discontinued.

As with other azoles, fluconazole may cause anaphylactic reactions in rare cases.

In rare cases, exfoliative skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have developed during treatment with fluconazole.

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.

In patients with invasive/systemic fungal infections, the rash should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme appear.

The concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be carefully controlled (see section “Interaction with other medicinal products”).

In common with other azoles, fluconazole may cause prolongation of QT interval on ECG. During fluconazole use, QT interval prolongation and ventricular fibrillation or flutter have been observed very rarely in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy contributing to such disorders. Therefore, in these patients with potentially proarrhythmic conditions, fluconazole should be used with caution.

Patients with liver, heart and kidney disease are advised to consult a physician before using the drug.

There have been reported cases of superinfections caused by Candida strains other than Candidaalbicans, which are often naturally resistant to fluconazole (e.g., Candidakrusei). In such cases, alternative antifungal therapy may be necessary.

Impact on ability to drive vehicles and mechanisms

Synopsis

Contraindications

– Concomitant use of terfenadine (with multiple fluconazole doses of 400 mg/day or more) (see “Interaction with other medicinal products.

– Hypersensitivity to fluconazole and other components of the drug or similar azole compounds;

– Children under 18 years of age;

– Period of lactation (see section “Use during pregnancy and breast-feeding.

– Concomitant use with drugs that increase the QT interval and are metabolized with CYP3A4 isoenzyme, such as cisapride, astemizole, erythromycin, pimozide, quinidine and amiodarone (see “Interaction with other compounds”).

Galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution

– Impaired liver function;

– Concurrent use of potentially hepatotoxic drugs;

– Alcoholism;

– Proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalances, concurrent use of drugs that cause arrhythmias);

– Impaired renal function;

– Rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections;

– Concurrent use of terfenadine and fluconazole at a dose less than 400 mg/day.

Side effects

Classification of adverse reactions by organ and system is given by frequency of occurrence: Very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000), including individual reports whose frequency is unknown (frequency cannot be estimated from available data). Tolerability of the drug is generally very good. The following adverse reactions have been reported in clinical and post-marketing (*) studies of fluconazole:

Nervous system disorders: frequently, headache; infrequently, dizziness*, seizures*, change in taste*, paresthesia, insomnia, somnolence; rarely, tremor.

Gastro-intestinal disorders: frequently – abdominal pain, diarrhea, vomiting*, nausea; infrequently – flatulence, dyspepsia*, dry oral mucosa, constipation.

Liver and biliary tract disorders: frequent – increased serum aminotransferase activity (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), alkaline phosphatase; infrequent – jaundice*, cholestasis, increased bilirubin concentration; rare – hepatotoxicity, in some cases with fatal outcome, liver dysfunction*, hepatitis*, hepatocellular necrosis*, hepatocellular damage.

Dermal and

Subcutaneous and subcutaneous fatty tissue disorders: Frequent – rash; infrequent – skin itching, urticaria, increased sweating, drug-induced rash; rare – exfoliative skin lesions*, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, facial edema, alopecia*.

Blood and lymphatic system disorders*: rarely – leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Disorders of the immune system*: rarely – anaphylaxis (including angioedema, facial edema).

Cardiovascular system disorders*: rarely – prolongation of the QT interval in the ECG, pirouette-type ventricular tachycardia (see section “Cautions”).

Metabolic disorders*: rarely – increased concentration of cholesterol and triglycerides in plasma, hypokalemia.

Musculoskeletal system disorders: infrequent – myalgia.

Others: infrequent – weakness, asthenia, fatigue, fever, vertigo.

In some patients, especially those with serious illnesses such as HIV infection or cancer, changes in blood counts, renal function and liver function have been observed during treatment with fluconazole and similar drugs, but the clinical significance of these changes and their relationship to treatment have not been established.

If any of the side effects listed in the instructions are aggravated, or if any other side effects not listed in the instructions are noted, the physician should be informed immediately.

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage, forced diuresis.

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

Pregnancy use

There are no adequate and controlled studies of fluconazole use in pregnant women.

There is currently no evidence that low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) have an increased incidence of adverse pregnancy outcomes, or a relationship to any specific malformations in the child.

High doses (400-800 mg/day) of fluconazole have described several cases of multiple birth defects in infants whose mothers received fluconazole therapy for most or all of the first trimester.

The use of the drug in pregnant women is not advisable, except for severe or life-threatening forms of fungal infections, if the anticipated benefit to the mother exceeds the possible risk to the fetus.

Women of childbearing age should use contraception.

Fluconazole is present in breast milk at the same concentration as in plasma, so it is contraindicated during lactation.

Similarities