Flukorus

General characteristics. Structure:

Active agent: флуконазол - 0,2 g. Excipients: sodium chloride - 0,9 g, water for injections - to 100 ml.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a new class of triazolny antifungal means. Possesses highly specific action, inhibiting activity of enzymes of the mushrooms dependent on P450 cytochrome. Blocks transformation of a lanosterol of cells of mushrooms into ergosterol; increases permeability of a cellular membrane, breaks its growth and replication. Flukonazol, being high-selective for P450 cytochrome of mushrooms, this practically does not oppress enzymes in a human body (in comparison with itrakonazoly, Clotrimazolum, ekonazoly and ketokonazoly to a lesser extent suppresses oxidizing processes, dependent on P450 cytochrome, in microsomes of a liver of the person). Has no anti-androgenic activity. It is active at the opportunistic mycoses including caused by Candida spp. (including generalized forms of candidiasis against the background of an immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp., at the local mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including at an immunosuppression). 

Pharmacokinetics. After intravenous administration флуконазол well gets into fabrics and liquids of an organism. Distribution Concentration in plasma is in direct proportionality from a dose. Concentration of active agent in breast milk, joint liquid, saliva, a phlegm and peritoneal liquid are similar to that in plasma. In stalemate liquid, epidermis and a corneous layer (the selection accumulation) the concentration exceeding serumal are reached. Well gets into cerebrospinal fluid, at fungal meningitis concentration in cerebrospinal fluid makes about 85% of that in plasma. About 90% of equilibrium concentration of drug in plasma (Css) are reached by 4-5 day. Introduction of the "shock" dose (in the first day) twice exceeding a usual daily dose allows to reach the concentration corresponding to 90% of Css by 2nd day. The seeming volume of distribution (Vd) approaches the general content of liquid in an organism. Communication with proteins of plasma low - 11-12%. Metabolism and removal the Elimination half-life (T1/2) - 30 h. Is CYP2C9 isoenzyme inhibitor in a liver. It is removed, preferential, by kidneys (80% - in not changed look, 11% - in the form of metabolites). The clearance of a flukonazol is proportional to clearance of creatinine. The pharmacokinetics of a flukonazol significantly depends on a functional condition of kidneys, at the same time there is inverse relation between T]/2 and the clearance of creatinine (CC). After a hemodialysis, during 3 h concentration of a flukonazol in plasma decreases by 50%. The pharmacokinetics of a flukonazol is similar at intravenous administration and intake that allows to pass easily from one type of reception to another.

Indications to use:

- A cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), as at patients with a normal immune response, and at patients with various forms of immunosuppression (including patients have AIDS, at organ transplantation); a maintenance therapy for the purpose of prevention of a recurrence of a cryptococcosis at patients AIDS.
- Generalized candidiasis, including a kandidemiya, the disseminated candidiasis and other forms of an invasive candidosis infection, such as infections of a peritoneum, endocardium, eyes, bronchopulmonary system and uric ways, including at the patients with malignant tumors who are in intensive care units, the patients receiving cytotoxic or immunosutgressivny means and also at patients with other factors contributing to development of candidiasis.
- Prevention of candidiasis with high risk of a generalized infection, for example at patients, from expressed or it is long the remaining neutropenia.
- Deep local mycoses (кокцидиомикоз, паракокцидиомикоз, a sporotrichosis and histoplasmosis) at patients with normal immunity.
- Orofaringealny candidiasis, candidiasis of a gullet and mucous membranes at children.

Route of administration and doses:

Intravenously kapelno with a speed no more than 200 mg/hour. The daily dose of a flukonazol depends on character and weight of a fungal infection. At transfer from intravenous administration into reception of tablets and vice versa there is no need to change a daily dose. Treatment can be begun before obtaining results of crops and other laboratory researches. However therapy needs to be changed as appropriate when results of these researches become known.

Adult
- At cryptococcal meningitis and cryptococcal infections of other localizations in the first day appoint, on average, 400 mg of a flukonazol, and then continue treatment in a dose of 200-400 mg of 1 times a day. Treatment duration at cryptococcal infections depends on the clinical performance confirmed with a mycologic research; at cryptococcal meningitis it is usually continued by at least 6-8 weeks.
- For prevention of a recurrence of cryptococcal meningitis at patients AIDS after end of a full course of primary treatment. Therapy flukonazoly in a dose of 200 mg/days can be continued during very long term (transition to a peroral form is possible).
- At a kandidemiya, the disseminated candidiasis and other invasive candidosis infections the dose makes, on average, 400 mg in the first days, then - on 200 mg a day. At insufficient clinical performance the dose of a flukonazol can be increased to 400 mg/days. Duration of therapy depends on clinical performance. - For prevention of candidiasis with high risk of a generalized infection, for example at patients, from expressed or it is long the remaining neutropenia, the recommended dose makes 400 mg of 1 times a day. Flukonazol appoint some days before the expected emergence of a neutropenia and after increase in number of neutrophils more 1000/mkl continue treatment during 7 days. 
 - At deep local mycoses use of drug in a dose of 200-400 mg/days within 2 years can be required. Duration of therapy is determined individually; it makes at a coccidioidomycosis - 11-24 months, at a paracoccidioidomycosis - 2-17 months, at a sporotrichosis - 1-16 months and at histoplasmosis - 3-17 months (transition to a peroral form is possible).

To children

At children, as well as at similar infections at adults, duration of treatment depends on clinical and mycologic effect. At children drug should not be used in a daily dose which would exceed that at adults, that is no more than 400 mg a day. Drug is used daily 1 time a day. In need of performing long therapy transition to a peroral form of a flukonazol is possible.

- At cryptococcal meningitis and cryptococcal infections of other localizations, and also at generalized candidiasis at children the recommended dose makes 6-12 mg/kg/days, depending on disease severity. Длительностъ therapies - within 10-12 weeks (before laboratory confirmation of lack of activators in liquor).
- For prevention of a recurrence of cryptococcal meningitis at children, patients AIDS, after end of a full course of primary treatment flukonazoly in a dose of 6 mg/kg/days it is possible to continue therapy during long term.
- At oropharyngeal candidiasis at children the recommended dose makes 6 mg/kg in the first day, further daily on 3 mg/kg/days, once. Therapy duration - within not less than 2 weeks.
- At candidiasis of mucous membranes at children the recommended dose of a flukonazol makes 3 mg/kg/days. In the first day the shock dose of 6 mg/kg for the purpose of more bystry achievement of constant equilibrium concentration can be appointed. Therapy duration - not less than 3 weeks.
- At gullet candidiasis at children флуконазол it is appointed once in a daily dose of 3 mg/kg. In the first day the shock dose of 6 mg/kg/days can be appointed. Depending on disease severity the dose can be raised to 6-12 mg/kg/days. Therapy duration - not less than 3 weeks and within 2 weeks after regression of symptoms.
- For prevention of fungal infections at children with reduced immunity at which the risk of development of an infection is connected with the neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy флуконазол it is appointed once in daily doze3-12 mg/kg/days. Therapy duration - before elimination of the induced neutropenia.
 
At use of drug for children aged since the neonatality period to 4 nedelsledut to mean what at newborns флуконазол is removed slowly. In the first 2 weeks of life drug is appointed in the same dose (in mg/kg), as to children of more advanced age, but with an interval of 72 h. To children aged up to 4 weeks the same dose is entered with an interval of 48 h.
Use for elderly people.
In the absence of renal failures it is necessary to adhere to the usual mode of a drug dosing. Patients with a renal failure (KK less than 50 ml/min.) should correct the mode of dosing, as shown below.
Use of drug for patients with renal failures. 
At KK less than 50 ml/min. are required correction of the mode of dosing.

Flukonazol is brought generally with urine in not changed look. At a single dose change of a dose is not required. At patients with renal failures at repeated use of drug it is necessary to enter originally a shock dose from 50 mg to 400 mg then the daily dose (depending on indications) is determined by the following table.

Clearance of creatinine (ml/min.)                               Percent of the recommended dose
less than 50>                                                                             100%
more than 50 (without dialysis)                                                            50%
The patients residing on dialysis       of 100% after each session of dialysis

Flukonazol is entered intravenously kapelno with a speed no more than 200 mg/hour. At transfer of the patient from intravenous administration on administration of drug inside or on the contrary change of a daily dose is not required.
At children with renal failures the daily dose of drug should be reduced (in the same proportional dependence, as at adults), in compliance with degree of manifestation of a renal failure. 
Drug contains 0,9% chloride sodium solution; in 100 ml of drug about 15 mmol of ions of sodium and chlorine contain, therefore, at patients who need restriction of consumption of sodium or liquid, it is necessary to consider liquid rate of administering.

Features of use:

Treatment needs to be continued before emergence of kliniko-hematologic remission.
The premature termination of treatment leads to a recurrence.
Treatment can be begun in the absence of results of crops or other laboratory analyses, but at their existence the corresponding correction of antifungal therapy is recommended. During treatment it is necessary to control  blood indicators, function of kidneys and a liver.
Control of a prothrombin ratio at simultaneous use with anticoagulants of a coumarinic row is necessary. At emergence of renal failures and a liver it is necessary to stop administration of drug.
In rare instances use of a flukonazol was followed by toxic changes of a liver.
In case of the hepatotoxic effects connected with flukonazoly dependence of their development on the general daily dose, duration of therapy, a floor, and age of the patient is noted.
The hepatotoxic action of a flukonazol usually was reversible; its signs disappeared after the therapy termination. At emergence of clinical signs of damage of a liver which can be connected with flukonazoly drug should be cancelled.
Patients AIDS are more inclined to development of heavy skin reactions at use of many drugs. When at patients with a superficial fungal infection rash develops, and it is regarded as definitely connected with flukonazoly, drug should be cancelled. At emergence of rash in patients with system fungal infections, patients should be observed carefully and at emergence of violent changes or a mnogoformny erythema флуконазол it is necessary to cancel.
It is recommended to exercise control of concentration of cyclosporine in blood at the patients receiving флуконазол as at patients with the replaced kidney reception of a flukonazol in a dose of 200 mg/days leads to slow increase in concentration of cyclosporine in plasma. It is necessary to be careful at a concomitant use of a flukonazol with tsizapridy, rifabutiny or other drugs which are metabolized system of P450 cytochrome.
Influence on ability to driving of motor transport and to control of mechanisms
Experience of use of a flukonazol demonstrates that deterioration in ability to drive the car and mechanisms, connected with drug, is improbable.

Side effects:

Flukonazol, as a rule, is well had.
Depending on the frequency of emergence allocate the following groups of side effects: frequent - more than 1%, infrequent - 0,1-1%, rare - 0,01-0,1%, very rare - less than 0,01%.
Allergic reactions: infrequently - skin rash, it is rare - a multiformny exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease), anaphylactoid reactions (including the Quincke's disease, swelled persons, urticaria, a skin itch).
From the central nervous system: infrequently - a headache, dizziness, it is rare - spasms.
From the alimentary system: infrequently - nausea, diarrhea, a meteorism, an abdominal pain, taste change, vomiting, it is rare - an abnormal liver function (jaundice, a hyperbilirubinemia, increase in activity of alaninetransferase, an asparagintransferaza and alkaline phosphatase, hepatitis, a hepatocellular necrosis), including with a lethal outcome.
From bodies of a hemopoiesis: seldom - a leukopenia, thrombocytopenia, a neutropenia, an agranulocytosis.
From cardiovascular system: seldom - increase in duration of an interval of QT, is very rare - blinking/trembling of ventricles.
Others: seldom - a renal failure, an alopecia, a hypercholesterolemia, a gipertriglitseridemiya, a hypopotassemia.

Interaction with other medicines:

Anticoagulants. Flukonazol increases a prothrombin time of coumarinic anticoagulants (for example, warfarin) on average by 12% therefore careful control of a prothrombin time at the patients receiving флуконазол and coumarinic anticoagulants is necessary.
Peroral hypoglycemic drugs derivative of sulphonylurea (Chlorproramidum, Glibenclamidum, глипизид and Tolbutamidum). At their concomitant use with flukonazoly the elimination half-life of the peroral ginoglikemichesky drugs derivative of sulphonylurea, is extended that can lead to development of a hypoglycemia. It is necessary to control periodically concentration of glucose in blood and, if necessary, to make dose adjustment of hypoglycemic medicines.
The hydrochlorothiazide increases concentration of a flukonazol in plasma by 40%, but it does not demand change of the mode of dosing of a flukonazol from the patients receiving at the same time diuretics.
Phenytoinum. The concomitant use of a flukonazol and Phenytoinum is followed by increase in concentration of the last in clinically significant degree. Therefore monitoring of level of Phenytoinum and selection of its dose is necessary for ensuring therapeutic concentration in serum.
Oral contraceptives. Repeated use of a flukonazol (in doses of 50-200 mg) does not exert impact on efficiency of the combined oral contraceptives.
Rifampicin. Simultaneous use of a flukonazol and rifampicin led to decrease by 25% of AUC (the area under a pharmacokinetic curve) and for 20% of duration of an elimination half-life of a flukonazol. At co-administration of rifampicin and a flukonazol, it is necessary to increase a dose of a flukonazol.
Cyclosporine. At treatment flukonazoly it is recommended to control concentration of cyclosporine in blood.
Theophylline. Flukonazol extends an elimination half-life of theophylline and increases risk of development of intoxication (correction of its dose is necessary).
Terfenadin. The concomitant use of a flukonazol in doses of 400 mg / суг and more with terfenadiny is contraindicated. Treatment flukonazoly in doses less than 400 mg/days in combination with terfenadiny needs to be carried out under careful control of the doctor.
Tsizaprid. At a concomitant use of a flukonazol and a tsizaprid — undesirable reactions from heart, including paroxysms of ventricular tachycardia (torsade depointes).
Rifabutin. Simultaneous use of a flukonazol and rifabutin can lead to increase in serumal concentration of the last. At simultaneous use of a flukonazol and rifabutin uveitis cases are described. The patients who are at the same time receiving рифабутин and флуконазол need to be observed carefully.
Takrolimus. Flukonazol increases concentration of a takrolimus in this connection, the risk of nephrotoxic action increases.
Zidovudine. At the patients receiving a combination of a flukonazol and zidovudine it is observed uveyolicheny concentration of a zidovudine which is caused by decrease in transformation of the last into its main metabolite therefore it is necessary to expect increase in side effects of a zidovudine.
Midazolam. Flukonazol increases concentration of midazolam in this connection, the risk of development of psychomotor effects increases (it is most expressed at use of a flukonazol inside, than intravenously).

Contraindications:

Hypersensitivity to drug components (including to other azolny antifungal medicines); a concomitant use of a terfenadin (against the background of constant reception of a flukonazol in a dose of 400 mg/days and more) or an astemizola; lactation period. 
Use at pregnancy It is necessary to avoid use of a flukonazol at pregnancy, except for hard cases and potentially life-threatening fungal infections when the expected advantage of use of a flukonazol for mother exceeds possible risk for a fruit. As concentration of a flukonazol in breast milk and in plasma is identical, to use drug in the period of a lactation (during breastfeeding) - contraindicated.

Overdose:

Symptoms: hallucinations, paranoid behavior.
Treatment: symptomatic: artificial diuresis. The hemodialysis during 3 h reduces concentration in plasma approximately by 50%.

Storage conditions:

At a temperature not above 30 °C. To store in the places unavailable to children. 
Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Solution for инф. 2 mg/ml: фл. or quarrystone. 100 ml 1.