Flucostat^® (Capsules) Instructions for Use

Marketing Authorization Holder

Otisipharm, JSC (Russia)

Manufactured By

Pharmstandard JSC (Russia)

Labeled By

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole (Rec.INN registered by WHO)

Dosage Forms

	Flucostat®	Capsules 50 mg: 7 pcs.
		Capsules 150 mg: 1 pc.

Dosage Form, Packaging, and Composition

Capsules opaque, light pink/pinkish-brown in color, size #2; capsule contents – white or almost white powder.

Excipients: colloidal silicon dioxide (aerosil), corn starch, magnesium stearate, sodium lauryl sulfate, lactose.

Capsule shell composition gelatin, iron oxide red dye (E172), methylparahydroxybenzoate, propylparahydroxybenzoate, titanium dioxide (E171), acetic acid.

7 pcs. – blister packs (1) – cardboard packs.

Capsules opaque, white in color, size #0; capsule contents – white or almost white powder.

Excipients: colloidal silicon dioxide (aerosil), corn starch, magnesium stearate, sodium lauryl sulfate, lactose.

Capsule shell composition gelatin, methylparahydroxybenzoate, propylparahydroxybenzoate, titanium dioxide (E171), acetic acid.

1 pc. – blister packs (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; triazole and tetrazole derivatives

Pharmacological Action

Antifungal drug. Fluconazole is a representative of the triazole class of antifungal agents and is a potent selective inhibitor of sterol synthesis in fungal cells.

Active against opportunistic mycoses pathogens, including those caused by Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp. Activity of fluconazole has also been demonstrated in models of endemic mycoses, including infections caused by Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.

Pharmacokinetics

Absorption

After oral administration, Fluconazole is well absorbed. The bioavailability is 90%. The C_max of fluconazole in blood plasma after a single oral dose of 150 mg on an empty stomach is 90% of its plasma concentration after intravenous administration at a dose of 2.5-3.5 mg/L.

T_max is reached 0.5-1.5 hours after administration. Concurrent food intake does not affect absorption after oral administration.

Plasma concentration is directly proportional to the administered dose.

Distribution

90% of C_ss is achieved by day 4-5 of treatment with the drug (when taken once daily).

Administration of a loading dose (on day 1), twice the average daily dose, allows achieving 90% of C_ss level by day 2. The apparent V_d approaches the total body water content. Protein binding is 11-12%.

Fluconazole penetrates well into all biological fluids of the body. Concentrations of fluconazole in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid are about 80% of plasma levels.

High concentrations are achieved in the stratum corneum, epidermis, dermis, and sweat fluid, which exceed serum levels.

Elimination

T_1/2 is about 30 hours.

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. The clearance of fluconazole is proportional to the creatinine clearance. No fluconazole metabolites have been detected in the blood.

Indications

• Cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including lungs, skin), both in patients with a normal immune response and in patients with various forms of immunosuppression (including patients with AIDS, organ transplant recipients); the drug can be used for the prevention of cryptococcal infection in AIDS patients;
• Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection (including infections of the peritoneum, endocardium, eyes, respiratory and urinary tracts). Treatment can be carried out in patients with malignant neoplasms, patients in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in the presence of other factors predisposing to the development of candidiasis;
• Mucosal candidiasis, including oral cavity and pharynx (including atrophic oral candidiasis associated with wearing dentures), esophagus, non-invasive bronchopulmonary infections, candiduria; prevention of relapse of oropharyngeal candidiasis in AIDS patients;
• Genital candidiasis: treatment of vaginal candidiasis (acute and chronic recurrent), prophylactic use to reduce the frequency of relapses of vaginal candidiasis (3 or more episodes per year); candidal balanitis;
• Prevention of fungal infections in patients with malignant neoplasms who are predisposed to such infections as a result of cytotoxic chemotherapy or radiation therapy;
• Skin mycoses, including mycoses of the feet, body, groin area, pityriasis versicolor, onychomycosis and skin candidiasis;
• Deep endemic mycoses, including coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in immunocompetent patients.

ICD codes

Dosage Regimen

The drug is taken orally.

For adults with cryptococcal meningitis and cryptococcal infections of other localizations, 400 mg is prescribed on the first day, and then treatment is continued at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on clinical efficacy, confirmed by mycological examination; for cryptococcal meningitis, therapy is usually continued for at least 6-8 weeks.

For prevention of relapse of cryptococcal meningitis in AIDS patients, after completing a full course of primary treatment, fluconazole therapy at a dose of 200 mg/day can be continued for a long period.

For candidemia, disseminated candidiasis and other invasive candidal infections, the dose is an average of 400 mg on the first day, and then 200 mg/day. If clinical efficacy is insufficient, the dose may be increased to 400 mg/day. The duration of therapy depends on clinical efficacy.

For oropharyngeal candidiasis, the drug is prescribed at an average dose of 50-100 mg once a day; duration of therapy is 7-14 days. If necessary, in patients with severe immunodeficiency, treatment may be longer.

For atrophic oral candidiasis associated with wearing dentures, the drug is prescribed at an average dose of 50 mg once a day for 14 days in combination with local antiseptic agents for denture treatment.

For other localizations of candidiasis (except for genital candidiasis), for example, esophagitis, non-invasive bronchopulmonary lesion, candiduria, candidiasis of the skin and mucous membranes, the effective dose is an average of 50-100 mg/day with a treatment duration of 14-30 days.

For prevention of relapses of oropharyngeal candidiasis in AIDS patients after completing a full course of primary therapy, Fluconazole may be prescribed at 150 mg once a week.

For vaginal candidiasis, Fluconazole is taken as a single oral dose of 150 mg. To reduce the frequency of relapses of vaginal candidiasis, the drug can be used at 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 spp., Fluconazole is prescribed as a single dose of 150 mg orally.

For prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg once a day depending on the degree of risk of developing a fungal infection. In the presence of a high risk of generalized infection, for example, in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg once a day. Fluconazole is prescribed several days before the expected onset of neutropenia; after the neutrophil count increases above 1000/µL, treatment is continued for another 7 days.

For skin mycoses, including mycoses of the feet, smooth skin, groin area and skin candidiasis, the recommended dose is 150 mg once a week or 50 mg once a day. The duration of therapy in usual cases is 2-4 weeks, but for mycoses of the feet, longer therapy may be required (up to 6 weeks).

For pityriasis versicolor, the recommended dose is 300 mg once a week for 2 weeks; some patients require a third dose of 300 mg/week, while in some cases a single dose of the drug at 300-400 mg is sufficient. An alternative treatment regimen is the use of the drug at 50 mg once a day for 2-4 weeks.

For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (an uninfected nail grows out). Regrowth of fingernails and toenails normally takes 3-6 months and 6-12 months, respectively.

For deep endemic mycoses, the use of the drug at a dose of 200-400 mg/day for up to 2 years may be required. The duration of therapy is determined individually and is 11-24 months for coccidioidomycosis, 2-17 months for paracoccidioidomycosis, 1-16 months for sporotrichosis, and 3-17 months for histoplasmosis.

In children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used at a daily dose exceeding that in adults. Flucostat^® is used daily once a day.

For mucosal candidiasis, the recommended dose of fluconazole is 3 mg/kg/day. A loading dose of 6 mg/kg may be prescribed on the first day to achieve steady-state concentrations more quickly.

For the treatment of generalized candidiasis and cryptococcal infection, the recommended dose is 6-12 mg/kg/day depending on the severity of the disease.

For prevention of fungal infections in children with reduced immunity, in whom the risk of infection is associated with neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day depending on the severity and duration of induced neutropenia.

In children with impaired renal function, the daily dose of the drug should be reduced (in the same proportional relationship as in adults) according to the degree of renal failure.

In elderly patients without impaired renal function, the drug is used according to the usual dosage regimen.

In patients with impaired renal function, no dose adjustment of the drug is required for a single dose. For multiple use of the drug in patients with creatinine clearance greater than 50 ml/min, the drug is prescribed at the average dose. For creatinine clearance from 11 to 50 ml/min, a loading dose of 50 mg to 400 mg should first be prescribed, followed by a dose that is 50% of the recommended dose. For patients who regularly undergo dialysis, one dose of the drug is prescribed after each hemodialysis session.

Adverse Reactions

From the digestive system taste alteration, nausea, flatulence, vomiting, abdominal pain, diarrhea; rarely – impaired liver function (jaundice, hepatitis, hepatocellular necrosis, hyperbilirubinemia, increased ALT, AST, ALP activity).

From the central nervous system headache, dizziness; rarely – seizures.

From the hematopoietic system rarely – leukopenia, thrombocytopenia, agranulocytosis.

From the cardiovascular system increased QT interval duration, ventricular fibrillation, ventricular flutter.

Allergic reactions skin rash; rarely – malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactoid reactions.

From metabolism rarely – hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Other rarely – impaired renal function, alopecia.

Contraindications

• Concomitant use of drugs that prolong the QT interval (including terfenadine or astemizole);
• Children under 3 years of age;
• Hypersensitivity to the drug or structurally related azole compounds.

With caution, the drug should be used in hepatic and/or renal failure, simultaneously with potentially hepatotoxic drugs, in alcoholism, in case of proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs that cause arrhythmias).

Use in Pregnancy and Lactation

The use of Flucostat^® during pregnancy is possible only in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment outweighs the possible risk to the fetus.

Since Fluconazole is excreted in breast milk in concentrations close to plasma concentrations, it is not recommended to prescribe the drug during breastfeeding.

Use in Hepatic Impairment

With caution, the drug should be used in hepatic failure, simultaneously with potentially hepatotoxic drugs, in alcoholism.

If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued.

Use in Renal Impairment

Patients with renal failure (creatinine clearance <50 ml/min) require dosage regimen adjustment.

Fluconazole is excreted mainly unchanged in the urine. For a single dose, no dose adjustment is required. In patients (including children and the elderly) with impaired renal function upon repeated administration of the drug, a loading dose of 50 mg to 400 mg should initially be administered.

For creatinine clearance >50 ml/min, the average recommended dose of the drug is used; for creatinine clearance from 11 to 50 ml/min, a dose that is 50% of the recommended dose is used. For patients regularly undergoing hemodialysis, one dose of the drug is administered after each hemodialysis session.

Pediatric Use

Contraindication: children under 3 years of age.

Geriatric Use

In elderly patients without impaired renal function, the drug is used according to the usual dosage regimen.

Special Precautions

In rare cases, the use of fluconazole has been accompanied by toxic liver changes, including fatalities, mainly in patients with serious concomitant diseases. No clear relationship between the incidence of hepatotoxic effects of fluconazole and the total daily dose, duration of therapy, gender and age of the patient has been noted. The hepatotoxic effect of fluconazole is usually reversible; its signs disappeared after discontinuation of therapy. If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued.

AIDS patients are more prone to developing severe skin reactions when using many drugs. If a patient receiving treatment for a superficial fungal infection develops a rash that can be associated with fluconazole use, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and Fluconazole should be discontinued if bullous lesions or erythema multiforme occur.

Caution should be exercised when using fluconazole concomitantly with cisapride, astemizole, rifabutin, tacrolimus, or other drugs metabolized by the cytochrome P450 enzyme system.

Overdose

Symptoms: hallucinations, paranoid behavior.

Treatment: gastric lavage and symptomatic therapy are recommended. Since Fluconazole is excreted by the kidneys, forced diuresis increases its elimination. Hemodialysis for 3 hours reduces the plasma concentration of fluconazole by approximately 50%.

Drug Interactions

Concomitant use of fluconazole with warfarin resulted in a 12% increase in prothrombin time. Therefore, it is recommended to monitor prothrombin time in patients receiving Flucostat^®® in combination with coumarin anticoagulants.

Concomitant use of Fluconazole increases the T_1/2 of oral hypoglycemic drugs – sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, and tolbutamide). Concomitant administration of fluconazole and oral hypoglycemic drugs is permissible, but the possibility of hypoglycemia should be considered.

Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentration. Therefore, if concomitant use of these drugs is necessary, monitoring of phenytoin concentration with dose adjustment is required to ensure therapeutic plasma levels.

Concomitant use of fluconazole and rifampicin leads to a 25% decrease in AUC and a 20% shortening of the T_1/2 of fluconazole in plasma. Therefore, in patients receiving rifampicin concomitantly, the dose of fluconazole is recommended to be increased.

It is recommended to monitor blood cyclosporine concentration in patients receiving Fluconazole, because when using fluconazole and cyclosporine in kidney transplant patients, fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine plasma concentration.

Patients receiving high doses of theophylline, or those with a potential risk of theophylline intoxication, should be monitored for early detection of theophylline overdose symptoms, as concomitant administration of fluconazole leads to a decrease in the mean plasma clearance rate of theophylline.

Cases of adverse cardiac reactions, including paroxysms of ventricular tachycardia (torsades de pointes type arrhythmia), have been reported with the concomitant use of fluconazole and terfenadine or cisapride.

There are reports of an interaction between fluconazole and rifabutin, accompanied by an increase in serum levels of the latter. Cases of uveitis have been reported with the concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and Fluconazole concomitantly should be carefully monitored.

Concomitant use of fluconazole and zidovudine results in an increase in zidovudine plasma concentration, which is caused by a decrease in its conversion to its metabolite.

Concomitant use of fluconazole with midazolam increases the risk of psychomotor effects; with tacrolimus it increases the risk of nephrotoxicity.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is approved for use as an over-the-counter product.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.