FLIFON [Fluconazole] 200 mg Solution for IV infusion

FLIFON

instructions for medical use of the drug

Tradename

Flifon, Флифон

International non-proprietary name

Fluconazole, Флуконазол

Composition:

Each vial (100 ml solution) contains:

active ingredient: fluconazole 200 mg

Excipients: sodium chloride, water for injection

Dosage form

Solution for infusion.

Pharmacotherapeutic group

Antifungal agent .

Pharmacological properties

Pharmacodynamics

Antimycotics for systemic use, triazole derivatives. Fluconazole is a triazole antifungal agent. Its main mode of action is to inhibit fungal cytochrome P -450-mediated alpha-lanosterol 14 demethylation, which is an essential step in fungal ergosterol biosynthesis. Accumulation of 14 alpha-methylstyrenes correlates with subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole.

Fluconazole has been shown to be more selective for fungal cytochrome P -450 enzymes than for various mammalian cytochrome P -450 enzyme systems. Does not have anti-adrogenic activity.

Active in opportunistic mycoses, incl. caused by Candida spp. (including generalized forms of candidiasis on the background of immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Mycrosporum spp. and Trichophyton spp.; with endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).

Pharmacokinetics

After intravenous administration, fluconazole penetrates well into tissues and body fluids.

Plasma concentration is directly proportional to the dose. The concentration of the active substance in breast milk, joint fluid, saliva, sputum and peritoneal fluid are similar to those in plasma.

In the sweat fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved. It penetrates well into the cerebrospinal fluid, with flexible meningitis, the concentration in the cerebrospinal fluid is about 85% of that in plasma.

90% C _ss of fluconazole in plasma is achieved by 4-5 days. The introduction of a "shock" dose (on the first day), 2 times the usual daily dose, allows you to reach a concentration corresponding to 90% C _ss by day 2.

The apparent V _d approaches the total fluid content in the body. Communication with plasma proteins is low -11-12%.

T _1/2 - 30 hours. It is an inhibitor of the CYP2C9 isoenzyme in the liver. It is excreted mainly by the kidneys (80% unchanged, 11% as metabolites). Fluconazole clearance is proportional to creatinine clearance.

The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, while there is an inverse relationship between and creatinine clearance (CC). After hemodialysis, within 3 hours, the concentration of fluconazole in plasma is reduced by 50%.

The pharmacokinetics of fluconazole are similar for internal administration and oral administration, which makes it easy to switch from one type of application to another.

Indications for use

·   cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), both in patients with a normal immune response and in patients with various forms of immunosuppression (including AIDS patients, with organ transplantation);

·   maintenance therapy to prevent recurrence of cryptococcosis in AIDS patients;

·   generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive kakdidiasis infection, such as infections of the peritoneum, endocardium, eyes, bronchopulmonary system and urinary tract, incl. in patients with malignant tumors in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis;

·   prevention of candidiasis in the presence of a high risk of generalized infection, for example, in patients with severe or long-lasting neutropenia;

·   deep endemic mycoses (coccidioidomycosis and histoplasmosis) in patients with normal immunity;

·   oropharyngeal candidiasis, candidiasis of the esophagus and mucous membranes.

Contraindications

·   hypersensitivity to the components of the drug, as well as to other antifungal agents - azole derivatives;

·   simultaneous use of terfenadine (against the background of continuous use of fluconazole at a dose of 400 mg / day or more) or astemizole;

·   lactation period.

Dosage and administration

Before use, the product must be checked visually for the absence of insoluble particles, discoloration and violations of the integrity of the package.

The solution for infusion is administered intravenously at a rate not exceeding 200 mg/h.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. When transferring from intravenous administration to the use of the drug in the form intended for oral administration, and vice versa, there is no need to change the daily dose.

adults

With cryptococcal meningitis and cryptococcal infections of other localizations , an average of 400 mg of fluconazole is prescribed on the first day, and then treatment is continued at a dose of 200-400 mg 1 time / day. The duration of treatment for cryptococcal infections depends on clinical efficacy, confirmed by mycological examination; in cryptococcal meningitis , it is usually continued for at least 6-8 weeks.

To prevent the recurrence of cryptococcal meningitis in patients with AIDS, after completing the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can be continued for a very long time (a switch to an oral form is possible).

The appearance of neutropenia and after an increase in the number of neutrophils more than 1000/μl, treatment is continued for another 7 days.

With 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 is with coccidioidomycosis - 11-24 months, with histoplasmosis - 3-17 months (a transition to the oral form is possible).

Children

As with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. For children, the daily dose of the drug should not exceed that for adults. Fluconazole is used daily 1 time per day.

With candidiasis of the mucous membranes , the recommended dose of the drug is 3 mg / kg / day. On the first day, in order to more quickly achieve constant Css, a loading dose of 6 mg / kg can be prescribed.

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

For the prevention of fungal infections in immunosuppressed patients in whom the risk of infection is associated with neutropenia that develops as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg / kg / day, depending on the severity and duration of induced neutropenia.

Use in children aged 4 weeks or less

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

Use in the elderly

In the absence of signs of renal failure, the drug is prescribed in the usual dose. In patients with renal insufficiency (Cl creatinine <50 ml / min), the dose of the drug is adjusted as described below.

Use in patients with renal insufficiency

With a single dose, dose changes are not required. In patients (including children) with impaired renal function, if repeated use of the drug is necessary on the first day of treatment, an initial dose of 50-400 mg should be used, depending on the indications. After that, the daily dose (depending on the indications) is set as follows:

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis. On the day when dialysis is not performed, the patient should receive a dose adjusted depending on the creatinine clearance.

Use in patients with liver failure

Flifon should be used with caution in patients with impaired liver function, since information on the use of the drug in this category of patients is not enough.

Special instructions and precautions

Treatment should be continued until the appearance of clinical and hematological remission. Premature termination of treatment leads to relapses. Treatment can be started if culture or other laboratory results are not available, but appropriate adjustment of antifungal therapy is recommended if available.

During treatment, it is necessary to monitor blood parameters (cellular composition, coagulability), kidney and liver function. It is necessary to control the prothrombin index with simultaneous use with indirect anticoagulants - coumarin derivatives. If there is a violation of the function of the kidneys and liver, the use of the drug should be discontinued.

With the appearance of bullous changes or erythema multiforme, it is necessary to stop taking the drug.

Caution must be exercised when fluconazole is co-administered with cisapride, rifabutin, or other drugs metabolized by the cytochrome P450 system.

Influence on the ability to drive vehicles and mechanisms

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

Use during pregnancy and during breastfeeding

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

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

Interaction with other drugs:

When using fluconazole with warfarin, the prothrombin time increases (by an average of 12%). It is recommended to control prothrombin time when fluconazole is combined with coumarin anticoagulants.

Fluconazole increases T _1/2 of the plasma 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 mellitus is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.

The simultaneous use of fluconazole and phenytoin can lead to an increase in plasma concentrations of phenytoin to a clinically significant degree. Therefore, if it is necessary to use these drugs together, it is necessary to monitor the concentration of phenytoin with dose adjustment in order to maintain the concentration of the drug within the therapeutic interval.

The combination with rifampicin leads to a decrease in AUC by 25% and a shortening of T _1/2 of fluconazole from plasma by 20%. Therefore, in patients receiving concomitant rifampicin, it is advisable to increase the dose of fluconazole.

It is recommended to control the concentration of cyclosporine in the blood in patients receiving fluconazole, because. when using fluconazole and cyclosporine in patients with a transplanted kidney, taking fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in plasma.

Patients who receive high doses of theophylline or who are likely to develop theophylline intoxication should be monitored for symptoms of theophylline overdose, tk. simultaneous administration of fluconazole leads to a decrease in the clearance of theophylline from blood plasma.

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

In patients receiving a combination of fluconazole and zidovudine, there is an increase in the concentration of zidovudine, which is caused by a decrease in the conversion of the latter to its main metabolite, so an increase in the side effects of zidovudine should be expected.

With the simultaneous use of fluconazole, terfenadine and cisapride, cases of adverse reactions from the heart, including torsades de pointes, have been described.

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

Increases the concentration of midazolam, and therefore increases the risk of developing psychomotor effects (more pronounced when fluconazole is used orally than intravenously).

Increases the concentration of tacrolimus, and therefore increases the risk of nephrotoxicity.

Side effect

Depending on the frequency of occurrence, the following groups of side effects are distinguished: often - more than 1%, infrequently - 0.1-1%, rarely - .0.01-0.1%; very rarely - less than 0.01%.

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

From the side of the central nervous system: infrequently - headache, dizziness; rarely - convulsions.

From the digestive system: