Flukonazol of 50 mg

General characteristics. Structure:

Active ingredient: флуконазол – 0,050 g or 0,150 g;

excipients: lactoses monohydrate (sugar milk) – 0,1804 g or
 0,19265 g, starch prezhelatinizirovanny – 0,0012 g or 0,00175 g, povidone (polyvinylpirrolidone low-molecular) – 0,0012 g or 0,00175 g, silicon dioxide colloid (aerosil) – 0,0048 g or 0,00035 g, magnesium stearate - 0,0024 g or 0,0035 g;

structure of a gelatin capsule: for a dosage of 50 mg - the case: gelatin – 0,038102 g, titanium dioxide of E 171 - 0,000778 g, a lid: gelatin - 0,022513 g, titanium dioxide of E 171 - 0,000462 g, dye ferrous oxide of yellow E 172 - 0,000145 g; for a dosage of 150 mg - the case: gelatin – 0,045408 g, titanium dioxide of E 171 - 0,000461 g, dye ferrous oxide of yellow E 172 - 0,000231 g; lid: gelatin - 0,029648 g, titanium dioxide of E 171 - 0,000301 g, dye ferrous oxide of yellow E 172 - 0,000151 g.

Description. Solid gelatin capsules No. 2 opaque white color with a lid of yellow color (for a dosage of 50 mg) or solid gelatin capsules No. 1 opaque yellow color with a lid of yellow color (for a dosage of 150 mg). Contents of capsules – powder of color, white or white with a yellowish shade.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a class of triazolny antifungal means, is powerful selection inhibitor of synthesis of sterol in a cell of mushrooms. Drug is effective at opportunistic mycoses, including the caused Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp. Also activity of a flukonazol on models of endemic mycoses, including the infections caused by Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum is shown.

Pharmacokinetics. After intake флуконазол it is well soaked up, its bioavailability – 90 %. The maximum concentration after intake on an empty stomach of 150 mg makes 90 % of content in plasma at intravenous administration in a dose of 2,5 - 3,5 mg/l. The concomitant use of food does not influence absorption of the drug accepted inside. The maximum concentration is reached in 0,5-1,5 h after reception, the elimination half-life of a flukonazol makes about 30 hours. Concentration in plasma are in directly proportional dependence on a dose. 90 % the level of equilibrium concentration are reached by 4-5 day of treatment by drug (at reception of 1 times/days).

Introduction of the "shock" dose (in the first day) twice exceeding a usual daily dose allows to reach the level corresponding to 90 % of equilibrium concentration, by second day. The obvious volume of distribution approaches the general content of water in an organism. Linkng with proteins of plasma - 11-12 %.

Flukonazol well gets into all biological liquids of an organism. Concentration of drug in saliva and a phlegm are similar to that in plasma. At patients with fungal meningitis the maintenance of a flukonazol in cerebrospinal fluid reaches 80 % of level it in plasma.

In a corneous layer, epidermis, a derma and stalemate liquid high concentration which exceed serumal are reached.

Is CYP2C9 isoenzyme inhibitor in a liver.

The pharmacokinetics of a flukonazol significantly depends on a functional condition of kidneys, at the same time there is inverse relation between an elimination half-life and the clearance of creatinine (CC). Flukonazol is brought generally by kidneys; about 80 % of the entered dose are removed with urine in not changed look. Metabolites of a flukonazol in peripheral blood are not revealed.

Indications to use:

- a cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including 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); drug can be used for prevention of a cryptococcal infection at patients AIDS;

- generalized candidiasis, including a kandidemiya, the disseminated candidiasis and other forms of invasive candidosis infections (an infection of a peritoneum, an endocardium, eyes, respiratory and uric ways). Treatment can be carried out at patients with malignant new growths, sick intensive care units, the patients taking a course of cytostatic or immunosuppressive therapy and also in the presence of other factors contributing to development of candidiasis;

- candidiasis of mucous membranes, including oral cavities and drinks (including the atrophic candidiasis of an oral cavity connected with carrying dentures, orofaringealny candidiasis), a gullet, noninvasive bronchopulmonary candidiases, a kandiduriya, skin candidiases; prevention of a recurrence of oropharyngeal candidiasis at patients AIDS;

- genital candidiasis: vaginal candidiasis (acute and chronic recuring), preventive use for the purpose of reduction of frequency of a recurrence of vaginal candidiasis (3 and more episodes a year); candidosis balanitis;

- prevention of fungal infections at patients with malignant new growths which are predisposed to such infections as a result of chemotherapy with cytostatics or radiation therapy;

- skin mycoses, including mycoses of feet, bodies, inguinal area; chromophytosis, onychomycosis; skin candidiasis;

- deep local mycoses, including кокцидиомикоз, паракокцидиомикоз, a sporotrichosis and histoplasmosis at patients with normal immunity.

Route of administration and doses:

Route of administration inside.

The adult at cryptococcal meningitis and cryptococcal infections of other localizations in the first day usually appoint 400 mg, and then continue treatment in a dose
200-400 mg of 1 times/days. Treatment duration at cryptococcal infections depends on the clinical performance confirmed with a mycologic research; at cryptococcal meningitis it is usually continued, at least, by 6-8 weeks.

For prevention of a recurrence of cryptococcal meningitis at patients AIDS, after end of a full course of primary treatment, флуконазол appoint in a dose 200 mg/days during a long span.

At a kandidemiya, the disseminated candidiasis and other invasive candidosis infections the dose usually makes 400 mg in the first days, and then – on 200 mg. At insufficient clinical performance the dose of drug can be increased to 400 mg/days. Duration of therapy depends on clinical performance.

At oropharyngeal candidiasis drug is usually appointed on 50-100 mg of 1 times/days; treatment duration - 7-14 days. If necessary, at patients with the expressed decrease in immunity treatment can be longer.

For prevention of a recurrence of oropharyngeal candidiasis at patients about AIDS after end of a full course of primary therapy drug can be appointed on 150 mg once a week.

At the atrophic candidiasis of an oral cavity connected with carrying dentures флуконазол usually appoint on 50 mg of 1 times/days within 14 days in combination with local antiseptic agents for processing of a prosthesis.

At other localizations of candidiasis (except for genital candidiasis), for example at an esophagitis, noninvasive bronchopulmonary damage, a kandiduriya, candidiasis of skin and mucous membranes, etc., the effective dose usually makes 50-100 mg/days lasting treatment of 14-30 days.

At vaginal candidiasis флуконазол accept once inside in a dose 150 mg. For decrease in frequency of a recurrence of vaginal candidiasis drug can be used in a dose of 150 mg once a month. Duration of therapy is determined individually; it varies from 4 to 12 months. More frequent use can be required by some patients.

At the balanitis caused by Candida флуконазол appoint once in a dose 150 mg inside.

For prevention of candidiasis the recommended dose of a flukonazol makes 50-400 mg
1 times/days depending on a risk degree of development of a fungal infection. With high risk of a generalized infection, for example at patients from the expected expressed or it is long the remaining neutropenia, the recommended dose makes 400 mg
1 time/days Flukonazol appoint some days before the expected emergence of a neutropenia; after increase in number of neutrophils ^{more than 1000/mm3} treatment is continued within 7 days.

At skin mycoses, including mycoses of feet, skin of inguinal area and skin candidiases the recommended dose makes 150 mg once a week or 50 mg of 1 times/days. Therapy duration in everyday occurences makes 2-4 weeks, however at mycoses of feet longer therapy can be required (up to 6 weeks).

At a chromophytosis - 300 mg once a week within 2 weeks, some patients need the third dose of 300 mg a week while regarding cases it is sufficient a single dose of 300-400 mg; the alternative scheme of treatment is use on 50 mg within 2-4 weeks once a day.

At an onychomycosis the recommended dose makes 150 mg once a week. Treatment should be continued before substitution of the infected nail (growth of not infected nail). Repeated growth of nails on fingers of hands and feet normal requires 3-6 months and
6-12 months respectively.

At deep local mycoses use of drug in a dose of 200-400 mg/days during up to 2 years can be required. Duration of therapy is determined individually; it can make 11-24 months at a koktsidiomikoza; 2-17 months at a parakoktsidiomikoza; 1-16 months at a sporotrichosis and 3-17 months at histoplasmosis.

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. Drug is used daily
1 times/days.

At candidiasis of mucous membranes 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.

For treatment of generalized candidiasis or a cryptococcal infection (including meningitis) the recommended dose makes 6-12 mg/kg/days within 10-12 weeks (before laboratory confirmation of lack of activators in liquor).

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 drug is appointed on 3-12 mg/kg/days depending on expressiveness and duration of preservation of the induced neutropenia.

At children with disturbances of functions of kidneys the daily dose of drug should be reduced
(in the same proportional dependence, as at adults), according to degree of manifestation of a renal failure.

At patients of advanced age in the absence of renal failures it is necessary to adhere to the usual mode of a drug dosing. Patients with a renal failure (clearance of creatinine less than 50 ml/min.) should correct the mode of dosing, as shown below.

Use of drug for patients with renal failures.

Flukonazol is brought generally with urine in not changed look. At its single dose change of a dose is not required. At repeated purpose of drug patients with an impaired renal function should enter at first a "shock" dose from 50 mg to 400 mg. If the clearance of creatinine (CC) makes more than 50 ml/min., the usual dose of drug (100 % of the recommended dose) is applied. At KK from 11 to 50 ml/min. the dose equal of 50 % recommended is applied. The patient who is regularly on dialysis, one dose of drug is applied after each session of a hemodialysis.

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 at lack of results of crops or other laboratory analyses, but at their existence the corresponding correction of fungicidal therapy is recommended.

During treatment it is necessary to control indicators of blood, function of kidneys and a liver. 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, including with a lethal outcome, mainly at patients with serious associated diseases. In case of the hepatotoxic effects connected with flukonazoly explicit dependence them from the general daily dose, duration of therapy, gender 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 invasive/system fungal infections, they should be observed and cancelled carefully флуконазол at emergence of violent changes or a mnogoformny erythema.

It is necessary to be careful at a concomitant use of a flukonazol with tsizapridy, rifabutiny or other drugs which are metabolized system _{of P 450 cytochrome}.

Influence on ability to manage vehicles, mechanisms.

Flukonazol does not influence ability to manage vehicles and to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

From the alimentary system: nausea, vomiting, taste change, diarrhea, a meteorism, abdominal pains, an abnormal liver function (jaundice, a hyperbilirubinemia, increase in activity of alaninaminotranspherases, aspartate aminotransferases, increase in activity of an alkaline phosphatase, hepatitis, гепатонекроз) including with a lethal outcome.

From a nervous system: headache, dizziness, spasms.

From bodies of a hemopoiesis: leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From cardiovascular system: increase in duration of an interval
Q-T, blinking/trembling of ventricles.

Allergic reactions: skin rash, malignant exudative erythema (Stephens-Johnson's syndrome), toxic epidermal necrolysis (Lyell's disease), anaphylactoid reactions (including Quincke's disease, face edema, small tortoiseshell, skin itch).

Others: renal failure, alopecia, hypercholesterolemia, gipertriglitseridemiya, hypopotassemia.

Interaction with other medicines:

At use of a flukonazol with warfarin the prothrombin time increases
(on average for 12 %). In this regard it is recommended to watch carefully indicators of a prothrombin time at the patients receiving drug in combination with coumarinic anticoagulants.

Flukonazol increases plasma elimination half-life of peroral hypoglycemic means - sulphonylurea derivatives (Chlorproramidum, Glibenclamidum, глипизид, Tolbutamidum) at healthy people. Combined use of a flukonazol and peroral gipoglikemiziruyushchy means at patients with diabetes is allowed, however, the doctor has to mean a possibility of development of a hypoglycemia.

Simultaneous use of a flukonazol and Phenytoinum can lead to increase of concentration of Phenytoinum in plasma to clinically significant degree. Therefore in need of combined use of these drugs it is necessary to monitorirovat concentration of Phenytoinum with correction of its dose for the purpose of maintenance of level of drug within a therapeutic interval.

The combination with rifampicin leads to decrease in AUC by 25 % and shortening of an elimination half-life of a flukonazol from plasma for 20 %. Therefore the patient receiving at the same time rifampicin, it is reasonable to increase a dose of a flukonazol.

It is recommended to exercise control of concentration of cyclosporine in blood at the patients receiving флуконазол since use of a flukonazol and cyclosporine for patients with the replaced kidney leads reception of a flukonazol in a dose of 200 mg/days to slow increase in concentration of cyclosporine in plasma.

Patients who receive high doses of theophylline or who have a probability of development of teofillinovy intoxication have to be under observation for the purpose of early identification of symptoms of overdose of theophylline since reception of a flukonazol leads to decrease in average speed of clearance of theophylline from plasma.

At simultaneous use of a flukonazol and tsizaprid cases of undesirable reactions from heart are described, including paroxysms of ventricular tachycardia (torsades de points).

There are messages on the interaction of a flukonazol and a rifabutin which was followed by increase in serumal levels of the last. At simultaneous use of a flukonazol and rifabutin uveitis cases are described. It is necessary to observe carefully the patients who are at the same time receiving рифабутин and флуконазол.

At the patients receiving a combination of a flukonazol and a zidovudine increase in 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 is observed.

Flukonazol increases concentration of midazolam – increase in risk of psychomotor effects (it is more expressed at use of a flukonazol inside); a takrolimusa – risk of nephrotoxicity.

The hydrochlorothiazide increases concentration of a flukonazol in plasma by 40 %.

Contraindications:

- 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 astemizol and other drugs extending Q-T interval;

- hypersensitivity to drug or relatives on structure to azolny connections;

- deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption;

- children's age (up to 3 years).

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage, artificial diuresis. The hemodialysis during 3 h reduces concentration in plasma approximately by 50 %.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

Without recipe

Packaging:

Capsules of 50 mg and 150 mg. On 1, 4, 7 or 10 capsules in a blister strip packaging. On 1, 2 or 4 blister strip packagings together with the application instruction in a pack from a cardboard.