Forcan^® (Capsules, Solution) Instructions for Use

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

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

The drug is effective in opportunistic mycoses, 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, Coccidiodes immitis and Histoplasma capsulatum.

Pharmacokinetics

After oral administration, Fluconazole is well absorbed, its bioavailability is 90%. C_max after oral administration on an empty stomach of 150 mg is 90% of the plasma concentration after intravenous administration at a dose of 2.5-3.5 mg/l. Concurrent food intake does not affect the absorption of the drug taken orally. T_max is 0.5-1.5 hours after administration, T_1/2 of fluconazole is about 30 hours. Plasma concentrations are directly proportional to the dose. The 90% steady-state concentration level is reached by day 4-5 of treatment with the drug (when taken once a day).

Administration of a loading dose (on the first day), twice the usual daily dose, allows achieving a level corresponding to 90% of the steady-state concentration by the second day. The apparent volume of distribution approaches the total water content in the body. Binding to plasma proteins is 11-12%.

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

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

Fluconazole is excreted mainly by the kidneys, approximately 80% of the administered dose is excreted in the urine unchanged. The clearance of fluconazole is proportional to the creatinine clearance. No metabolites of fluconazole were detected in the peripheral 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 transplantation); the drug can be used as a maintenance therapy for the prevention of cryptococcal infection in AIDS patients;
• Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infections (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 undergoing cytostatic or immunosuppressive therapy, as well as in the presence of other factors predisposing to the development of candidiasis;
• Candidiasis of the mucous membranes, including the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, candidiasis of the skin and mucous membranes, as well as atrophic oral candidiasis associated with wearing dentures (treatment can be carried out in patients with normal or reduced immune function), prevention of recurrence of oropharyngeal candidiasis in AIDS patients;
• Genital candidiasis: vaginal candidiasis (acute and chronic recurrent), prophylactic use to reduce the frequency of recurrence 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 cytostatic chemotherapy or radiation therapy;
• Skin mycoses, including mycoses of the feet, body, groin area; pityriasis versicolor; onychomycosis; skin candidiasis;
• Deep endemic mycoses, including coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.

ICD codes

Dosage Regimen

Capsules

Adults

Orally.

For cryptococcal meningitis and cryptococcal infections of other localizations, 400 mg is usually 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, it is usually continued for at least 6-8 weeks. To prevent relapse of cryptococcal meningitis in AIDS patients, after completing a full course of primary treatment, Fluconazole is prescribed at a dose of 200 mg/day for a long period of time.

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

For oropharyngeal candidiasis, the drug is usually prescribed at 50-100 mg once a day; the duration of treatment is 7-14 days. If necessary, in patients with a pronounced decrease in immunity, treatment may be longer.

For atrophic oral candidiasis associated with wearing dentures, Fluconazole is usually prescribed at 50 mg once a day for 14 days in combination with local antiseptics 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, etc., the effective dose is usually 50-100 mg/day with a treatment duration of 14-30 days. To prevent recurrence of oropharyngeal candidiasis in AIDS patients after completing a full course of primary therapy, the drug can be prescribed at 150 mg once a week.

For vaginal candidiasis, Fluconazole is taken once orally at a dose of 150 mg. To reduce the frequency of recurrence 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, Fluconazole is prescribed once at a 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 a few days before the expected onset of neutropenia; after the neutrophil count increases above 1000/mm³, treatment is continued for another 7 days.

For skin mycoses, including mycoses of the feet, skin of the 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, however, for mycoses of the feet, longer therapy (up to 6 weeks) may be required.

For pityriasis versicolor, the recommended dose is 300 mg once a week for 2 weeks. Some patients require a third dose of 300 mg per week, while in some cases a single dose of 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, it may be necessary to use the drug at a dose of 200-400 mg/day for up to 2 years. The duration of therapy is determined individually; it can 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 with 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 that would exceed that in adults. The drug is used daily once a day.

For candidiasis of the mucous membranes, 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 or cryptococcal infection, the recommended dose is 6-12 mg/kg/day depending on the severity of the disease. For the 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 dependence as in adults), in accordance with the degree of renal failure.

In elderly patients without impaired renal function, the usual dosing regimen of the drug should be followed. For patients with renal failure (creatinine clearance less than 50 ml/min), the dosing regimen should be adjusted as indicated below.

Use of the drug in patients with impaired renal function

Fluconazole is excreted mainly in the urine unchanged. With a single dose, no dose adjustment is required. When the drug is repeatedly prescribed to patients with impaired renal function, a loading dose of 50 mg to 400 mg should first be administered. If CC is more than 50 ml/min, the usual dose of the drug is used (100% of the recommended dose). If CC is from 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used. For patients regularly undergoing dialysis, one dose of the drug is applied after each hemodialysis session.

Solution

Fluconazole in the form of a solution for infusion is administered intravenously by drip at a rate not exceeding 20 mg (10 ml)/min. When switching from intravenous administration to capsule intake and vice versa, there is no need to change the daily dose.

The infusion solution is compatible with the following solvents: 20% glucose solution, Ringer’s solution, Hartmann’s solution, potassium chloride in glucose solution, 4.2% sodium bicarbonate solution, aminofusin, isotonic sodium chloride solution.

Fluconazole infusions can be carried out using conventional transfusion sets, using one of the above liquids.

Use in adults

For cryptococcal infections, the usual dose of fluconazole is 400 mg once a day on the first day of treatment, then 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on clinical efficacy, confirmed by mycological examination, and is usually from 6 to 8 weeks.

For prevention of relapse of cryptococcal meningitis in AIDS patients after completing a full course of primary therapy, fluconazole is prescribed to the patient in doses of at least 200 mg/day for a long period.

For candidemia, disseminated candidiasis and other invasive candidal infections, the daily dose is 400 mg on the first day and 200 mg on subsequent days. Depending on the clinical efficacy of the drug, the dose can be increased to 400 mg/day. The duration of treatment depends on clinical efficacy.

For oropharyngeal candidiasis, including patients with immune disorders, the usual dose is 50-100 mg once a day for 7-14 days. If necessary, treatment can be extended, especially in cases of severe immune disorders.

For other candidal infections, for example esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the usual daily dose is 50-100 mg for 14-30 days.

For prevention of fungal infections in patients with malignant neoplasms, the dose of fluconazole should be 50 mg once a day as long as the patient is at increased risk due to cytostatic therapy or radiation therapy.

Use 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 in a daily dose exceeding that in adults. Fluconazole is used daily once a day. 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 the prevention of fungal infections in patients with reduced immunity, the drug is prescribed at 3-12 mg/kg/day.

In newborns, Fluconazole is excreted more slowly, so in the first 2 weeks of life, the drug is prescribed at the same dose (in mg/kg) as in older children, but at intervals of 72 hours. For children aged 3 and 4 weeks of life, the same dose is administered at intervals of 48 hours.

Use in the elderly

In the absence of renal impairment, the usual dosing recommendations for the drug should be followed. For patients with impaired renal function (creatinine clearance < 50 ml/min), the dosing regimen should be adjusted as indicated below.

Use in patients with renal failure

Fluconazole is excreted primarily in the urine unchanged. With a single dose, no dose adjustment is required. In patients (including children) with impaired renal function when taking the drug repeatedly, a “loading” dose of 50 mg to 400 mg should be initially administered. After the “loading” dose, the daily dose (depending on the indication) is determined according to the following table.

Adverse Reactions

From the digestive system taste change, nausea, vomiting, diarrhea, flatulence, abdominal pain, rarely – impaired liver function (hyperbilirubinemia, increased activity of alanine aminotransferase, aspartate aminotransferase, increased activity of alkaline phosphatase).

From the nervous system headache, rarely – convulsions, dizziness.

From the hematopoietic organs rarely – leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the cardiovascular system increased duration of the Q-T interval, ventricular fibrillation/flutter.

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

Other rarely – impaired renal function. Alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Contraindications

• Concomitant use of cisapride, terfenadine, astemizole and other drugs that prolong the QT interval;
• Pregnancy, lactation period;
• Children under 3 years of age (for this dosage form);
• Hypersensitivity to the drug or structurally related azole compounds.

With caution : hepatic insufficiency, appearance of rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, potentially 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 the drug in pregnant women is not advisable, except for severe or life-threatening forms of fungal infections, if the intended effect outweighs the possible risk to the fetus.

Fluconazole is present in breast milk at concentrations similar to those in plasma; therefore, its use during lactation is not recommended.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Fluconazole is eliminated primarily by the kidneys as unchanged drug. No adjustment in single dose is required. In patients with impaired renal function receiving multiple doses, an initial loading dose of 50 mg to 400 mg should be given. After the loading dose, the daily dose should be based on the following: For creatinine clearance (CrCl) greater than 50 mL/min, the usual dose is recommended (100% of the recommended dose). For CrCl between 11 and 50 mL/min, 50% of the recommended dose should be used. Patients on regular dialysis should receive one dose after each hemodialysis session.

Pediatric Use

Contraindicated in children under 3 years of age. In children, as in adults with similar infections, the duration of therapy is based on the clinical and mycological response.

Geriatric Use

In elderly patients with no evidence of renal impairment, the usual dosing regimen should be followed.

Special Precautions

In rare cases, the use of fluconazole has been associated with serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. No obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. Fluconazole-associated 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 severe hepatic injury. If clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole, it should be discontinued.

Patients with AIDS are more prone to the development of severe skin reactions to many drugs. If a rash develops in patients with superficial fungal infection that is considered attributable to fluconazole, the drug should be discontinued. If patients with invasive/systemic fungal infections develop a rash, they should be monitored closely and Fluconazole discontinued if bullous lesions or erythema multiforme develop. Caution should be exercised when fluconazole is co-administered with rifabutin, tacrolimus, or other drugs metabolized by the cytochrome P450 system.

Overdose

Symptoms hallucinations, paranoid behavior.

Treatment symptomatic and supportive therapy. Gastric lavage and forced diuresis may be beneficial. Hemodialysis for 3 hours reduces plasma concentrations by approximately 50%.

Drug Interactions

Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended.

Fluconazole increases the plasma half-life of concurrently administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide). When fluconazole is used concomitantly with these oral hypoglycemic agents, blood glucose concentrations should be carefully monitored, and the dose of the sulfonylurea should be adjusted as necessary. Concomitant use of fluconazole and phenytoin may increase phenytoin levels. Phenytoin concentrations should be monitored and the dose adjusted to maintain therapeutic levels.

Coadministration of rifampin with fluconazole resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. Consider increasing the dose of fluconazole when rifampin is administered concomitantly. Cyclosporine concentrations should be monitored in patients receiving Fluconazole and cyclosporine concomitantly, because in renal transplant patients, fluconazole at a dose of 200 mg/day slowly increases cyclosporine concentrations.

Patients receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, as it reduces the clearance of theophylline.

There have been reports of cardiac events, including cases of torsades de pointes, in patients receiving fluconazole and cisapride concomitantly.

There are reports of interaction between fluconazole and rifabutin, leading to increased serum levels of rifabutin. Uveitis has been reported in patients receiving fluconazole and rifabutin concomitantly. Patients receiving rifabutin and Fluconazole concomitantly should be carefully monitored.

An increase in zidovudine concentrations has been observed in patients receiving concomitant fluconazole and zidovudine, due to a decrease in the metabolism of zidovudine. Therefore, an increase in the frequency of zidovudine adverse reactions may occur.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

Over-the-counter.

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.