Flukonazol

General characteristics. Structure:

Active ingredient: 50 mg or 150 mg of a flukonazol in 1 capsule.

Excipients: starch corn, povidone (polyvinylpirrolidone low-molecular), calcium stearate.

Gelatinous solid capsules: titanium dioxide, dye blue patent, gelatin, preservatives - methylhydroxybenzoate, пропилгидроксибензоат.

Effective anti-mycotic broad-spectrum agent for treatment of mycoses of skin and nails, various forms of candidiasis.

Pharmacological properties:

Pharmacodynamics. Flukonazol, the representative of a class of triazolny antifungal means, is powerful selection inhibitor of fungal enzyme 14-α-demetilazy. Drug interferes with transition of a lanosterol to ergosterol – the main component of cellular membranes of mushrooms.

Drug is effective at opportunistic mycoses, including the caused Candida spp. (Candida albicans, Candida tropicalis), 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 (Cmax) after intake, on an empty stomach 150 mg makes 90% of content in plasma at intravenous administration in a dose of 2,5 - 3,5 mg/kg. The concomitant use of food does not influence absorption of the drug accepted inside. Concentration in plasma reaches peak in 0,5-1,5 h (TCmax) after reception. Concentration in plasma are in direct proportionality from a dose. 90% the level of equilibrium concentration are reached by 4-5 day of treatment by drug (at reception of 1 times/days).

Use in the first day of the dose twice exceeding a usual daily dose allows to reach drug level in plasma, equal 90% to value of equilibrium concentration, by second day. The obvious volume of distribution approaches the total amount of water in an organism. Linkng with proteins of plasma small - 11-12%.

Flukonazol well gets into all biological liquids of an organism, including liquor. Concentration of drug in saliva and a phlegm are similar to its levels 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.

Less than 5% of a flukonazol are metabolized at the first passing through a liver. The elimination half-life (T1/2) of a flukonazol makes about 30 h Flukonazol is brought generally by kidneys; about 80% of the entered dose are removed by kidneys in not changed look. The clearance of a flukonazol is proportional to clearance of creatinine. 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 with 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), 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 a coccidioidomycosis, a paracoccidioidomycosis, a sporotrichosis and histoplasmosis at patients with normal immunity.

Route of administration and doses:

The daily dose depends on character and weight of a fungal infection.

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 of 200-400 mg 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. Duration of administration of drug is defined by the doctor.

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; at heavy system candidiasis – increase in a dose up to 800 mg a day is possible. Duration of therapy depends on clinical performance; it is necessary to continue not less than 2 weeks after receiving a negative hemoculture or after disappearance of symptoms of a disease.

At oropharyngeal candidiasis drug is usually appointed on 50-100 mg by 1 times/days; treatment duration - 7-14 days. If necessary, at patients with the expressed decrease in immunity treatment can be longer (3 weeks).

At the atrophic candidiasis of an oral cavity connected with carrying dentures флуконазол usually appoint 50 mg 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 heavy mucous candidiasis – 100-200 mg/days. 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. Duration of treatment is defined by the doctor.

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 флуконазол 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 times/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 are 1 times/days old. 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 coccidioidomycosis; 2-17 months at a paracoccidioidomycosis; 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 by 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 the recommended dose makes 6-12 mg/kg/days depending on disease severity.

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.

The maximum daily dose for children makes – 12 mg/kg.

Dosing for patients with a renal failure. Flukonazol is brought generally by kidneys in not changed look. At its single dose change of a dose is not required.

Adult patients with an impaired renal function at repeated purpose of drug should appoint 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 / мин.применяется the dose equal of 50% recommended, or a usual dose of 1 times in 2 days. The patient who is regularly on dialysis, one dose of drug is applied after each session of a hemodialysis.

At children with renal failures 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.

Features of use:

Pregnancy and period of a lactation: Use of drug for pregnant women is inexpedient, except for severe or life-threatening forms of fungal infections if the estimated effect exceeds possible risk for a fruit.

Flukonazol is found in breast milk in the same concentration, as well as in plasma therefore its appointment in the period of a lactation is not recommended.

Treatment can be begun in the absence of results of crops or other laboratory analyses, but at their existence the corresponding correction of fungicidal therapy is recommended.

As флуконазол it is removed preferential by kidneys, it is necessary to be careful at patients with a renal failure. At treatment by repeated doses of a flukonazol, dosing has to be carried out taking into account KK.

It is necessary to be careful at purpose of a flukonazol the patient with the broken function of a liver. During treatment it is regularly necessary to monitorirovat the level of "hepatic" enzymes and to make observation of the patient for the purpose of identification of possible toxic effects. At increase in level of "hepatic" enzymes the doctor has to weigh the benefit brought by the carried-out therapy and risk of development of severe damage of a liver. The hepatotoxic action of a flukonazol is usually reversible; symptoms disappear after the therapy termination.

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 control a prothrombin time at the patients who are at the same time receiving флуконазол and anticoagulants of a coumarinic row.

Treatment needs to be continued before emergence of kliniko-hematologic remission. The premature termination of treatment leads to a recurrence.

The dye which is a part of drug blue patent can cause allergic reaction.

Influence on ability to driving or other mechanical means: It is unknown of negative influence on ability of driving and work with other mechanisms.

Side effects:

From the alimentary system: nausea, diarrhea, a meteorism, vomiting, an abdominal pain, taste change, it is rare - increase in activity of "hepatic" enzymes and an abnormal liver function (jaundice, a hyperbilirubinemia, increase in activity of alaninaminotranspherase (ALT), asparaginaminotransferaz (nuclear heating plant) and the alkaline phosphatase (AP), hepatitis, a hepatocellular necrosis), including with a lethal outcome.

From a nervous system: headache, dizziness; seldom - spasms.

From bodies of a hemopoiesis: seldom – an agranulocytosis, a neutropenia. At patients with heavy fungal infections hematologic changes (a leukopenia and thrombocytopenia) can be noted.

From cardiovascular system: increase in duration of an interval of Q – T on the electrocardiogram (ECG), blinking/trembling of ventricles.

Allergic reactions: skin rash, a multiformny exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease), bronchial asthma (is more often at intolerance of acetylsalicylic acid), anaphylactoid reactions (including a Quincke's disease, a face edema, a small tortoiseshell, a skin itch).

Others: seldom - a renal failure, an alopecia, a hypercholesterolemia, a gipertriglitseridemiya, a hypopotassemia.

Interaction with other medicines:

The single dose of a flukonazol at treatment of vulval candidiasis is not followed by significant interactions. Nevertheless, at use of several or higher doses of drug along with other medicines the following medicinal interactions are possible:

· Interaction of a flukonazol with terfenadiny, tsizapridy and astemizoly can lead to increase in concentration of these drugs in plasma that in turn can become the reason of lengthening of an interval of QT and lead to serious violations of a cordial rhythm. Flukonazol inhibits P450 system enzymes in a liver, reducing, thus, metabolism of a terfenadin, tsizaprid and astemizol. Co-administration of fluconazole and these drugs is contraindicated.

· At joint purpose of warfarin and a flukonazol lengthening of a prothrombin time is noted. In this regard it is necessary to control a prothrombin time at the patients who are at the same time receiving флуконазол and anticoagulants of a coumarinic row.

· Fluconazole extends T1/2 of peroral hypoglycemic drugs (sulphonylurea derivatives). At patients with a diabetes mellitus it is possible to appoint at the same time флуконазол and sulphonylurea derivatives, however it is necessary to take possible risk of development of a hypoglycemia into account.

· It is necessary to take into account that at repeated co-administration of a hydrochlorothiazide and flukonazol, concentration of a flukonazol in plasma increases.

· Rifampicin accelerates metabolism of a flukonazol. It is necessary to raise as appropriate a dosage of a flukonazol at their simultaneous use.

· At the patients who transferred transplantation of kidneys флуконазол can increase concentration of cyclosporine in plasma. In this regard carrying out monitoring of concentration of cyclosporine at the patients who are at the same time receiving cyclosporine and флуконазол is recommended.

· Flukonazol increases concentration of theophylline in plasma. In this regard carrying out monitoring of concentration of theophylline at the patients who are at the same time receiving theophylline and флуконазол is recommended.

· Flukonazol can increase concentration in plasma of an indinavir and midazolam. At co-administration of these drugs with flukonazoly, their dosage has to be respectively reduced.

· Clinical trials showed that as a result of delay of metabolism of a zidovudine, its concentration in plasma at co-administration with flukonazoly can increase. Observation of the patients who are at the same time receiving both of these drugs as in this case the frequency of side effects of a zidovudine can increase is necessary.

· Flukonazol increases serumal concentration of Phenytoinum. At co-administration it is necessary to control doses of Phenytoinum and to respectively korregirovat them.

· Increases efficiency of a rifabutin (at simultaneous use uveitis cases are described) and Phenytoinum in clinically significant degree (at the combined use control of concentration of Phenytoinum in plasma is necessary).

· Increases concentration of a takrolimus – risk of nephrotoxicity.

Contraindications:

Hypersensitivity to a flukonazol, other components of drug or other azolny connections; a concomitant use of a terfenadin (against the background of constant reception of a flukonazol in a dose of 400 mg/days and more), a tsizaprid or an astemizol and other drugs extending an interval of QT and increasing risk of development of heavy disturbances of a rhythm; lactation period; children's age up to 3 years (for this dosage form).

With care: a liver and/or renal failure, emergence of rash against the background of use of a flukonazol for patients with a superficial fungal infection and invasive/system fungal infections, a concomitant use of a terfenadin and a flukonazol in a dose less than 400 mg/days, potentially proaritmogenny states at patients with multiple factors of risk (organic heart diseases, disturbances of electrolytic balance, a concomitant use of the medicines causing arrhythmias); patients with intolerance of acetylsalicylic acid, pregnancy.

Overdose:

Symptoms: nausea, vomiting, diarrhea, in hard cases can be noted spasms, hallucinations, paranoid behavior.

Treatment: symptomatic, gastric lavage; since флуконазол it is excreted by kidneys the artificial diuresis is recommended. The hemodialysis during 3 h reduces concentration in plasma twice.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use after a period of validity.

Issue conditions:

Without recipe

Packaging:

Capsules on 50 and 150 mg. On 1 capsule with a dosage of 150 mg or on 7 capsules with a dosage of 50 mg in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1 blister strip packaging together with the application instruction place in a pack from a cardboard.