Fluconazole 150mg capsules №2

Antifungal agent, has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450. Blocks the conversion of lanosterol of fungal cells into membrane lipid - ergosterol; increases the permeability of the cell membrane, violates its growth and replication.

Fluconazole, being highly selective for cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, Clotrimazole, econazole and Ketoconazole, to a lesser extent, it inhibits cytochrome P450-dependent oxidative processes in human liver microsomes). Does not possess antiadrogenic activity.

Active in opportunistic mycoses, incl. caused byCandida spp. (including generalized forms of candidiasis on the background of immunosuppression),Cryptococcus neoformans andCoccidioides immitis (including intracranial infections),Microsporum spp. andTrichophyton spp.; with endemic mycoses caused byBlastomyces dermatidis, Histoplasma capsulatum (including with immunosuppression).

Pharmacokinetics

After oral administration, fluconazole is well absorbed, food intake does not affect the rate of absorption of fluconazole, its bioavailability is 90%.

The time to reach the maximum concentration after oral administration on an empty stomach 150 mg of the drug - 0.5-1.5 hours, C_max is 90% of the concentration in plasma with the on / in the introduction of a dose of 2.5-3.5 mg / l T_1/2 Fluconazole is 30 hours. Communication with plasma proteins - 11-12%.Plasma concentration is directly dose dependent. 90% level of the equilibrium concentration is achieved by the 4th-5th day of drug treatment (when taken 1 time per day).

The administration of the loading dose (on the first day), which is 2 times higher than the usual daily, allows to reach the concentration level corresponding to 90% of the equilibrium concentration by the second day.

Fluconazole penetrates well into all biological fluids of the body. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to its plasma levels. Constant values ​​in vaginal secretion are reached 8 hours after ingestion and are held at this level for at least 24 hours. Fluconazole penetrates well into the cerebrospinal fluid (CSF) - with fungal meningitis the concentration in CSF is about 85% of its plasma level. In the sweat fluid, epidermis and the stratum corneum (selective accumulation) concentrations exceeding the serum levels are achieved. After ingestion of 150 mg on the 7th day, the concentration in the stratum corneum of the skin is 23.4 mcg / g, and 1 week after the second dose is taken - 7.1 mcg / g; concentration in the nails after 4 months of application at a dose of 150 mg 1 time per week - 4.05 mcg / g in healthy and 1.8 mcg / g in the affected nails. The volume of distribution is close to the total water content in the body.

It is an inhibitor of the isoenzyme CYP2C9 in the liver. Excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). Fluconazole clearance is proportional to creatinine clearance.No metabolites of fluconazole were detected in the peripheral blood.

The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between the half-life and creatinine clearance. After hemodialysis for 3 hours, plasma concentration of fluconazole is reduced by 50%.

Indications

• cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including light skin), both in patients with a normal immune response, and in patients with various forms of immunosuppression (including in AIDS patients, during organ transplantation ); the drug can be used to prevent cryptococcal infection in AIDS patients;
• generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infections (peritoneal, endocardial, eye, respiratory and urinary tract infections). The treatment can be carried out in patients with malignant neoplasms, patients in the intensive care unit, patients undergoing a course of cytostatic or immunosuppressive therapy, as well as in the presence of other factors predisposing to the development of candidiasis;
• mucosal candidiasis, incl. oral cavity and pharynx (including atrophic candidiasis of the oral cavity, associated with the wearing of dentures), esophagus, non-invasive bronchopulmonary candidiasis, candiduria, candidiasis of the skin; prevention of recurrence of oropharyngeal candidiasis in AIDS patients;
• genital candidiasis: vaginal candidiasis (acute and chronic recurrent), prophylactic use in order to reduce the frequency of recurrences of vaginal candidiasis (3 or more episodes per year); candidal balanitis;
• prevention of fungal infections in patients with malignant neoplasms, which are predisposed to such infections as a result of Chemotherapy with cytostatics or radiation therapy;
• mycoses of the skin, including mycoses of the feet, body, groin; scaly varicolor, onychomycosis; skin candidiasis;
• deep endemic mycoses, including coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.

Contraindications

• hypersensitivity to the drug (including to other azole antifungal drugs in history);
• simultaneous administration of terfenadine (against the background of continuous administration of fluconazole at a dose of 400 mg / day or more) or astemizole, as well as other drugs that prolong the QT interval;
• children's age up to 4 years.

Carefully: hepatic and / or renal failure, the appearance of a rash on the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, simultaneous administration of terfenadine and fluconazole at a dose of less than 400 mg / day, simultaneous administration of potentially hepatotoxic drugs, alcoholism, potentially proarrhythmogenic states in patients with multiple risk factors (organic heart disease, electrolyte imbalance, simultaneous administration of drugs causing arrhythmias), pregnancy.

Use during pregnancy and lactation

The use of the drug in pregnant women is impractical, with the exception of severe or life-threatening forms of fungal infections, when the potential benefit from the use of fluconazole for the mother far exceeds the risk to the fetus.

Since the concentration of fluconazole in breast milk and plasma is the same, it is contraindicated to use the drug during lactation.

Special notes

Treatment should continue until clinical and hematologic remission. Premature discontinuation of treatment leads to relapse.

During treatment, it is necessary to monitor blood counts, kidney and liver function. If you have any abnormalities in the kidneys and liver, you should stop taking the drug.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including fatal, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with fluconazole, they are not markedly dependent on the total daily dose, duration of therapy, sex and age of the patient. The hepatotoxic effect of fluconazole has usually been reversible; his symptoms disappeared after cessation of therapy. If clinical signs of liver damage appear that may be associated with fluconazole, the drug should be withdrawn.

AIDS patients are more likely to develop severe skin reactions with the use of many drugs. In cases where a rash develops in patients with a surface fungal infection and is regarded as definitely associated with fluconazole, the drug should be discontinued.When a rash appears in patients with invasive / systemic fungal infections, they should be carefully monitored and fluconazole should be canceled when a bullous change or erythema multiforme occurs.

Care must be taken when taking fluconazole with cisapride, rifabutin, or other drugs that are metabolized by the cytochrome P 450 system.

Composition

1 capsule contains:

Active ingredient: fluconazole 150 mg

Excipients:lactose monohydrate; pregelatinized starch; silica colloidal anhydrous; Magnesium stearate; sodium lauryl sulfate.

Dosage and administration

Inside

Adults and children over 15 years old (weighing more than 50 kg)for cryptococcal meningitis and cryptococcal infections of other localizations, 400 mg (8 capsules 50 mg) are usually prescribed on the first day, and then continue treatment at a dose of 200 mg (4 capsules 50 mg) - 400 mg (8 capsules 50 mg) 1 time per day. The duration of treatment for cryptococcal infections depends on the clinical efficacy confirmed by mycological examination; With cryptococcal meningitis, the treatment should be at least 6-8 weeks.

To prevent the recurrence of cryptococcal meningitis in AIDS patientsAfter completion of the full course of primary therapy, fluconazole is prescribed at a dose of 200 mg (4 capsules of 50 mg) per day for a long period of time.

For candidemia, disseminated candidiasis and other invasive candidal infections on the first day, the dose is 400 mg (8 capsules 50 mg each), and then 200 mg each (4 capsules 50 mg each) per day. With insufficient clinical efficacy, the dose of the drug can be increased to 400 mg (8 capsules of 50 mg) per day. The duration of therapy depends on the clinical effectiveness.

When oropharyngeal candidiasis the drug is usually prescribed 150 mg 1 time per day, the duration of treatment is 7-14 days. If necessary, in patients with a pronounced decrease in immunity, treatment may be longer.

For the prevention of recurrence of oropharyngeal candidiasis in AIDS patients after completion of the full course of primary therapy, 150 mg once a week.

With atrophic oral candidiasis associated with the wearing of dentures- 50 mg 1 time per day for 14 days in combination with local antiseptic drugs for the treatment of the prosthesis.

With other localizations of candidiasis (with the exception of genital)For example, for esophagitis, non-invasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is usually 150 mg / day for a duration of treatment of 14-30 days.

With vaginal candidiasis Fluconazole is taken once by mouth in a dose of 150 mg. To reduce the frequency of recurrences 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 need more frequent use.

With balanitis caused by Candida, fluconazole is administered orally once at a dose of 150 mg / day.

For the prevention of candidiasis The recommended dose is 50-400 mg 1 time per day, depending on the degree of risk of developing a fungal infection. For the prevention of candidiasis in patients with malignant tumors, the recommended dose of fluconazole is 150-400 mg 1 time per day, depending on the degree of risk of developing a fungal infection. If there is a high risk of generalized infection, for example, in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg / day. Fluconazole is prescribed a few days before the expected appearance of neutropenia; after an increase in the number of neutrophils of more than 1 thousand / μl, the treatment is continued for another 7 days.

In case of mycoses of the skin, including mycoses of the feet, skin of the groin area, and candidosis of the skin The recommended dose is 150 mg once a week or 50 mg once a day, the dosage regimen depends on the clinical and mycological effect. The duration of therapy in normal cases is 2-4 weeks, but with mycoses of the feet, longer therapy may be required (up to 6 weeks).

With pityriasis versicolor - 300 mg (2 capsules of 150 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 50 mg once a day for 2-4 weeks.

With onychomycosis The recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (the uninfected nail grows).Normally, it takes 3-6 months and 6-12 months for the nails to grow again on the fingers and feet.

With deep endemic mycoses may require the use of the drug in a dose of 200 mg (4 capsules 50 mg) - 400 mg (8 capsules 50 mg) per 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 childrenAs 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, i.e. no more than 400 mg / day. The drug is used daily 1 time per day.

Side effects

From the digestive system: loss of appetite, changes in taste, abdominal pain, vomiting, nausea, diarrhea, flatulence, rarely - impaired liver function (jaundice, hepatitis, hepatonecrosis, hyperbilirubinemia, increased alanine aminotransferase, aspartate aminotransferase, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased aspartate aminotransferase, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis, increased alkaline phosphatase, hepatocellular necrosis; h heavy

From the nervous system: headache, dizziness, excessive fatigue, rarely - seizures.

From the side of blood-forming organs: rarely - leukopenia, thrombocytopenia (bleeding, petechiae), neutropenia, agranulocytosis.

Allergic reactions: skin rash, rarely - erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (includingangioedema, swelling of the face, urticaria, itching of the skin).

Since the cardiovascular system: an increase in the duration of the QT interval, ventricular flicker / flutter.

Other: rarely, kidney dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Drug interaction

With the use of fluconazole with Warfarin, PV increases (on average by 12%). In this regard, it is recommended to closely monitor the performance of PV in patients receiving the drug in combination with coumarin anticoagulants.

Fluconazole increases the plasma half-life of oral hypoglycemic agents - sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy people. The combined use of fluconazole and oral hypoglycemic agents in patients with diabetes is allowed, but the physician should be aware of the possibility of hypoglycemia.

The simultaneous use of fluconazole and phenytoin can lead to an increase in plasma phenytoin concentration to a clinically significant extent. Therefore, if necessary, the joint use of these drugs need to monitor the concentration of phenytoin with the correction of its dose in order to maintain the level of the drug within the therapeutic interval.

The combination with rifampicin leads to a decrease in AUC by 25% and shortening of the half-life of fluconazole from plasma by 20%. Therefore, patients receiving rifampicin at the same time, it is advisable to increase the fluconazole dose.

It is recommended to monitor the concentration of cyclosporine in the blood of patients receiving fluconazole, sincethe use of fluconazole and cyclosporine in patients with a transplanted kidney (taking fluconazole at a dose of 200 mg / day) leads to a slow increase in plasma cyclosporine concentration.

Patients who receive high doses of theophylline or who are likely to develop theophylline intoxication should be monitored for the early detection of symptoms of a theophylline overdose, since receiving fluconazole leads to a decrease in the average rate of clearance of theophylline from plasma.

With simultaneous use of fluconazole with terfenadine and cisapride, cases of unwanted heart reactions, including paroxysmal ventricular tachycardia, are described (torsades de points).

The simultaneous use of fluconazole and hydrochlorothiazide can lead to an increase in plasma concentration of fluconazole by 40%.

There are reports of the interaction of fluconazole and rifabutin, accompanied by an increase in serum levels of the latter. With simultaneous use of fluconazole and rifabutin, cases of uveitis are described. It is necessary to carefully observe patients who simultaneously receive rifabutin and fluconazole.