Mycosyst, 150 mg capsules

Fluconazole is a representative of the class of triazole derivatives and is a selective inhibitor of sterol synthesis in the fungal cell. It blocks conversion of lanosterol of fungal cells into ergosterol; it increases cell membrane permeability. Fluconazole, being highly selective for cytochrome P450 of fungi, does not suppress cytochrome P450 system in humans (compared to itraconazole, clotrimazole, econazole and ketoconazole it suppresses cytochrome P450 dependent oxidation processes in human liver microsomes to a lesser extent). It has no androgenic activity.

The drug is active in mycosis caused by Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.

Pharmacokinetics

Fluconazole is well absorbed after oral administration, its bioavailability is 90%. T_max after oral administration on an empty stomach of 150 mg is 0.5-1.5 h, and C_max is 90% of the plasma concentration when administered by injection at a dose of 2.5-3.5 mg/kg. Concomitant ingestion does not affect the absorption of the drug taken orally.

Plasma concentrations are directly proportional to the dose. 90% C_ss is reached by day 4-5 of treatment with the drug (when taken once daily). Administration of a dose twice the usual daily dose on the first day allows achieving a plasma concentration of fluconazole equal to 90% of the C_ss value by day 2. The apparent V_d approaches the total body water content. Binding to plasma proteins is 11-12%.

Fluconazole penetrates well into all body fluids.

In the stratum corneum of the epidermis, dermis and sweat fluid high concentrations are achieved that exceed serum concentrations. After oral administration of 150 mg on day 7, the concentration in the stratum corneum of the skin is 23.4 µg/g, and 1 week after the second dose is 7.1 µg/g; the concentration in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 µg/g in healthy and 1.8 µg/g in the affected nails.

The drug concentrations in saliva, sputum, breast milk, joint and peritoneal fluid are similar to its plasma concentrations. In patients with fungal meningitis the content of fluconazole in cerebrospinal fluid reaches 80% of its concentration in plasma.

The constant values in vaginal secretion are reached 8 hours after oral administration and are maintained at this level for at least 24 hours. It is an inhibitor of CYP2C9 isoenzyme in the liver. Pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T_1/2 and creatinine clearance.

T_1/2 fluconazole is about 30 h. Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is excreted unchanged by the kidneys, 11% – as metabolites. Fluconazole clearance is proportional to creatinine clearance. No fluconazole metabolites were detected in peripheral blood.

In 3 hours after hemodialysis plasma concentration of fluconazole decreases by 50%.

Indications

Active ingredient

Composition

1 capsule contains:

The active ingredient:

fluconazole150 mg;

Associates:

colloidal silica;

magnesium stearate;

Talc;

povidone;

corn starch;

anhydrous lactose.

How to take, the dosage

Use in adults

In cryptococcal infections the usual dose of fluconazole is 400 mg once daily on the first day of treatment, thereafter 200-400 mg once daily. The duration of treatment in cryptococcal infections depends on the clinical efficacy confirmed by mycological study, and usually is from 6 to 8 weeks.

The recommended duration of treatment for therapy of cryptococcal meningitis is 10-12 weeks after a negative result of microbiological examination of the cerebrospinal fluid sample.

In order to prevent relapse of cryptococcal meningitis in AIDS patients after completion of complete primary therapy, fluconazole is given at a dose of at least 200 mg daily for an extended period.

In candidemia, disseminated candidiasis and other invasive candidiasis infections, the daily dose of fluconazole is 400 mg on the first day and 200 mg on subsequent days. If necessary, the drug dose may be increased to 400 mg/day. The duration of treatment depends on clinical efficacy.

In severe systemic candidiasis it is possible to increase the dose to 800 mg/day. Duration of therapy depends on clinical efficacy. It should be continued for at least 2 weeks after obtaining of negative hemoculture or after disappearance of disease symptoms.

In oropharyngeal candidiasis, including patients with immune disorders, the usual dose of fluconazole is 50-100 mg/day for 7-14 days. For prophylaxis of oropharyngeal candidiasis relapses in AIDS patients after full course of primary therapy, 150 mg once a week. If necessary, treatment may be prolonged, especially in case of severe immune disorders.

In atrophic oral candidiasis associated with the wearing of dentures, fluconazole is usually prescribed 50 mg/day for 14 days in combination with antiseptics for denture treatment.

In other candida infections such as esophagitis, non-invasive bronchopulmonary infections, candidiasis, candidiasis of the skin and mucous membranes, the daily dose is 50-100 mg for 14-30 days.

In severe candidiasis of mucous membranes 100-200 mg/day.

For prevention of fungal infections in patients with malignancies, the dose of fluconazole should be 50 mg/day as long as the patient is at high risk due to cytostatic or radiation therapy.

In case of vaginal candidiasis, 150 mg once. To reduce the recurrence rate, use 150 mg once a month for 4-12 months, sometimes more frequent use may be necessary.

For balanitis caused by Candida spp., fluconazole is prescribed once in a dose of 150 mg orally (capsules).

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg/day depending on the degree of risk of fungal infection. If there is a high risk of generalized infection, such as in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg/day. Fluconazole is prescribed several days before the expected appearance of neutropenia; after neutrophil count increases more than 1000/mm3 the treatment is continued for another 7 days.

In mycoses of the skin (including candidiasis), including mycoses of the feet, skin, and groin, the recommended dose is 150 mg once weekly or 50 mg/day. Duration of therapy in common cases is 2-4 weeks, but in case of mycoses of feet a longer therapy of up to 6 weeks may be required (capsules).

In pityriasis, 300 mg once weekly for 2 weeks; some patients require a third dose of 300 mg/week, but in some cases a single dose of 300 mg is sufficient; an alternative regimen is 50 mg/day for 2-4 weeks (capsules).

In onychomycosis, the recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced by a healthy nail. It normally takes 3-6 and 6-12 months respectively for re-growth of nails on fingers and feet (capsules).

In deep endemic mycosis, it may be necessary to use the drug at a dose of 200-400 mg/day for 2 years. The duration of therapy is determined individually; it can be 11-24 months in coccidioidosis; 2-17 months in paracoccidioidosis and 3-17 months in histoplasmosis.

Performance in children

The duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose higher than that of adults. Fluconazole is used daily once a day.

In mucosal candidiasis, the recommended dose of fluconazole is 3 mg/kg/day. A shock dose of 6 mg/kg may be administered on the first day in order to achieve Css more rapidly.

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 immunocompromised children whose risk of infection is associated with neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is indicated at 3-12 mg/kg/day, depending on the severity and duration of the induced neutropenia.

Interaction

Anticoagulants. In patients taking fluconazole and indirect coumarin anticoagulants, close monitoring of PV is necessary, because it may increase.

Sulfonylurea drugs. Fluconazole may prolong T1/2 sulfonylurea derivatives, therefore the possibility of hypoglycemia should be considered when using them concomitantly.

Phenytoin. Concomitant use of fluconazole and phenytoin may be accompanied by clinically significant increase in phenytoin concentration, which requires reducing its dose.

Rifampicin. Concomitant administration of rifampicin and fluconazole decreases Cmax and T1/2 of the latter, so the dose of fluconazole should be increased if combined use is necessary.

Rifabutin. Concomitant use of fluconazole and rifabutin is accompanied by an increase in serum concentration of the latter, it is possible to develop uveitis.

Cyclosporine. When co-administration of fluconazole and cyclosporine it is recommended to monitor the concentration of the latter in blood, because it may increase.

Terfenadine. Because of the occurrence of serious, life-threatening arrhythmias in patients taking antifungal agents – azole derivatives in combination with terfenadine, their combined use is contraindicated.

Cisapride. In concomitant use of fluconazole and cisapride there have been described the cases of adverse reactions of the heart, including paroxysms of ventricular tachycardia. Simultaneous use is contraindicated.

Zidovudine. When used in combination with fluconazole, an increase in plasma concentration of zidovudine is possible. Patients taking this combination should be monitored to detect side effects of zidovudine.

Theophylline. Administration of fluconazole leads to decreased average blood plasma clearance rate of theophylline; consequently, the risk of development of toxic effects of theophylline and its overdose increases.

Midazolam. Concomitant use of fluconazole and midazolam leads to a significant increase in plasma concentrations of the latter and risk of psychomotor reactions.

Hydrochlorothiazide. Concomitant administration of fluconazole and hydrochlorothiazide increases plasma concentrations of fluconazole by 40%.

Tacrolimus. Concomitant administration of fluconazole and tacrolimus increases the concentration of the latter in blood serum, which leads to an increased risk of nephrotoxicity.

We should use fluconazole with caution in patients receiving other drugs metabolized by cytochrome P450 system concomitantly.

Special Instructions

Treatment with fluconazole should be continued until clinical and hematological remission occurs. Premature discontinuation of treatment leads to relapses.

As fluconazole is mainly excreted by the kidneys, caution should be exercised in patients with renal insufficiency. During long-term treatment with fluconazole, dosing should be adjusted for creatinine clearance. In rare cases the use of fluconazole was accompanied by a toxic effect on the liver, including fatal, mainly in patients with serious comorbidities. It is necessary to monitor the liver function. If there are signs of liver damage, which may be associated with fluconazole administration, the drug should be stopped.

A rare cases of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients while taking the drug. Patients with AIDS and malignant neoplasms are more prone to develop severe skin reactions when using many drugs. If a patient develops a superficial fungal infection rash during treatment that may be associated with fluconazole use, the drug should be discontinued.

Patients with invasive/systemic fungal infections should be closely monitored and fluconazole should be discontinued if bullous lesions or erythema multiforme appear. Caution should be exercised when concomitant administration of fluconazole with rifabutin or other drugs metabolized by cytochrome P450 system.

PH should be monitored in patients receiving fluconazole and coumarin-type indirect anticoagulants concomitantly.

Impact on the ability to drive and operate other mechanical equipment.Patients should use caution when driving motor vehicles or operating machinery, because dizziness may occur during treatment with fluconazole.

Contraindications

With caution: hepatic and/or renal insufficiency; occurrence of rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections; simultaneous administration of fluconazole with rifabutin or other drugs metabolized by cytochrome P450 system isoenzymes; concomitant use of terfenadine and fluconazole in dose less than 400 mg/day; potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs that cause arrhythmias); intolerance of acetylsalicylic acid; pregnancy.

Side effects

Digestive system disorders: nausea, vomiting, diarrhea, flatulence, abdominal pain, change in taste, liver function disorders (hyperbilirubinemia, increased liver transaminases activity, alkaline phosphatase, jaundice, hepatitis, hepatocellular necrosis, including fatal).

Nervous system disorders: headache, dizziness, seizures.

Hematopoietic disorders: leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

Allergic reactions: skin rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactoid reactions (including angioedema).angioneurotic edema, facial edema, urticaria, skin itching), bronchial asthma (often with intolerance to acetylsalicylic acid).

Systemic diseases: prolongation of QT interval on ECG, ventricular fibrillation/tripping.

Others: impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Overdose

Symptoms: nausea, vomiting, diarrhea; in severe cases seizures, hallucinations, paranoid behavior may be noted.

Treatment: symptomatic (gastric lavage, forced diuresis, hemodialysis). After a 3-hour session of hemodialysis the plasma concentration of fluconazole decreases by approximately 50%.

Pregnancy use

The use of fluconazole during pregnancy is possible only when the potential benefit to the mother outweighs the risk to the fetus.

Fluconazole is detected in breast milk at the same concentration as in plasma, so its administration during lactation is contraindicated.

Similarities