Flukonazol

General characteristics. Structure:

50 mg: Active agent: флуконазол 50 mg; excipients: starch corn – 5 mg, silicon dioxide colloid – 1 mg, magnesium stearate – 1 mg, cellulose microcrystallic – 43 mg; gelatinous solid capsule of white color No. 3: gelatin – to 100%, titanium dioxide [E171] – 2,0%.

150 mg: Active agent: флуконазол 150 mg; excipients: starch corn – 15 mg, silicon dioxide colloid – 3 mg, magnesium stearate – 3 mg, cellulose microcrystallic – 129 mg; gelatinous solid capsule of yellow color No. 0: gelatin – to 100%, titanium dioxide [E171] – 1,3333%, dye quinolinic yellow [E104] – 0,9197%, dye a sunset yellow [E110] – 0,0044%.

Description. Dosage of 50 mg: capsules firm gelatinous No. 3 of white color. Contents of capsules – powder of color, white or white with a yellowish shade.
Dosage of 150 mg: capsules firm gelatinous No. 0 of yellow color. Contents of capsules – powder of color, white or white with a yellowish shade.

Pharmacological properties:

Pharmacodynamics. 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, practically does not oppress these 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 antiadrogenny 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 meningitis and encephalitis), Microsporum spp. and Trichophyton spp; at the local mycoses caused by Blastomyces dermatidis and Histoplasma capsulatum at the normal or suppressed immunity.

Pharmacokinetics. After intake флуконазол it is well soaked up, meal does not influence the speed of absorption of a flukonazol, its bioavailability – 90%.
Time of the maximum concentration (Cmax) after intake, on an empty stomach 150 mg of drug – 0,5-1,5 h also makes 90% of concentration in plasma at intravenous administration in a dose of 2,5-3,5 mg/l. An elimination half-life (Т½) the flukonazola makes about 30 h. Communication with proteins of plasma – 11-12%. Concentration in plasma is in direct 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 a day).
Use in the first day of the dose twice exceeding a usual daily dose allows to reach the level of concentration of a flukonazol in plasma, the corresponding 90% of equilibrium concentration, by second day.
Flukonazol well gets into all biological liquids of an organism. Concentration of active agent of drug in breast milk, joint liquid, saliva, a phlegm and peritoneal liquid is similar that in a blood plasma. Constant values in a vaginal secret are reached in 8 h after intake and keep at this level not less than 24 h Flukonazol well gets into cerebrospinal fluid (SMZh), at fungal meningitis concentration in SMZh makes about 80% of its level in plasma. In stalemate liquid, epidermis and in a corneous layer (the selection accumulation) the concentration exceeding serumal are reached.
After intake of 150 mg for the 7th day concentration in a corneous layer of a derma – 23,4 mkg/g, and in 1 week after reception of the second dose – 7,1 mkg/g; concentration in nails after 4 months of use in a dose of 150 mg once a week – 4,05 mkg/g in healthy and 1,8 mkg/g – in the affected nails. The seeming volume of distribution approaches the general content of water in an organism.
Less than 5% of a flukonazol are metabolized at the first passing through a liver. Flukonazol is brought preferential by kidneys (80% – in an invariable look, 11% – in the form of metabolites). The clearance of a flukonazol is proportional to clearance of creatinine. Metabolites of a flukonazol in peripheral blood are not revealed.
The pharmacokinetics of a flukonazol significantly depends on a functional condition of kidneys, at the same time there is an inversely proportional dependence between an elimination half-life and clearance of creatinine. After a hemodialysis during 3 h concentration of a flukonazol in a blood plasma decreases by 50%.

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 an immunosuppression (including at patients with 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 urinary tract). 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 of patients with 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, trunks, inguinal area; scaly (multi-colored) deprive, an onychomycosis, skin candidiasis;
– deep local mycoses, including кокцидиомикоз and histoplasmosis at patients with normal immunity.

Route of administration and doses:

Inside. The daily dose depends on character and weight of a fungal infection.
To adults and children 15 years are more senior (body weight more than 50 kg) at cryptococcal meningitis and cryptococcal infections of other localizations in the first day usually appoint 400 mg (8 capsules on 50 mg), and then continue treatment in a dose of 200 mg (4 capsules on 50 mg) – 400 mg (8 capsules on 50 mg) 1 time a day. Treatment duration at cryptococcal infections depends on the clinical performance confirmed with a mycologic research; at cryptococcal meningitis the course of treatment has to be not less than 6-8 weeks. For prevention of a recurrence of cryptococcal meningitis at patients with AIDS, after end of a full course of primary therapy, флуконазол appoint in a dose 200 mg (4 capsules on 50 mg) in days during a long span.

At a kandidemiya, the disseminated candidiasis and other invasive candidosis infections in the first days the dose makes 400 mg (8 capsules on 50 mg), and then – on 200 mg (4 capsules on 50 mg) in days. At insufficient clinical performance the dose of drug can be increased to 400 mg (8 capsules on 50 mg) in days. Duration of therapy depend on clinical performance.
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. For prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS
after end of a full course of primary therapy – on 150 mg once a week.
At the atrophic candidiasis of an oral cavity connected with carrying dentures – 50 mg of 1 times a day within 14 days in combination with local antiseptic medicines 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 and so on, the effective dose usually makes 50-100 mg/days lasting treatment of 14-30 days; at heavy candidiasis of mucous membranes – 100-200 mg/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 from 4 to 12 months. More frequent use can be required by some patients.
At the balanitis caused by Candida spp., флуконазол appoint inside once in a dose 150 mg a day.
For prevention of candidiasis the recommended dose – 50-400 mg of 1 times a day depending on a risk degree of development of a fungal infection. For prevention of candidiasis at patients with malignant new growths the recommended dose of a flukonazol makes 150-400 mg of 1 times a day 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 – 400 mg/days. Flukonazol appoint some days before the expected emergence of a neutropenia. After increase in number of neutrophils more than 1 thousand / мкл treatment is continued within 7 days.
At skin mycoses, including mycoses of feet, skin of inguinal area, candidiases
bones the recommended dose makes 150 mg once a week or 50 mg of 1 times a day, the mode of dosing depends on clinical and mycologic effect. 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 (2 capsules on 150 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 of 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 mg (4 capsules on 50 mg) – 400 mg (8 capsules on 50 mg) in days during up to 2 years can be required. Duration of therapy is determined individually: it can make 11-24 months at a coccidioidomycosis 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. Drug is used daily 1 time a day, the maximum daily dose makes 12 mg/kg.
At candidiasis of mucous membranes the recommended dose of a flukonazol makes
3 mg/kg a day. In the first day the shock dose of 6 mg/kg for the purpose of more bystry achievement of equilibrium concentration can be appointed.
For treatment of generalized candidiasis or at a cryptococcal infection the recommended dose makes 6-12 mg/kg a day 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 a day depending on expressiveness and duration of preservation of an indutsiroyovanny neutropenia.
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 from renal
insufficiency (clearance of creatinine less than 50 ml/min.) the mode of dosing follows
to correct, as shown below.
Flukonazol is brought generally with urine in not changed look. At a chronic renal failure the "shock" dose – 50-400 mg is originally entered. 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. 50% of the recommended dose or a usual dose of 1 times in 2 days are applied.
To patients with an impaired renal function флуконазол enter on following
to the scheme:

Clearance of a krestinin                         Interval / daily dose

•> 40 ml/min.                             • 24 hours (usual mode of dosing)
 
• 21-40 ml/min.                          • 48 hours (1 time in 2 days) or a half
                                                   usual daily dose (1 times at 24 o'clock)

• 10-20 ml/min.                          • 72 hours (1 time in the 3rd days) or a third of usual
                                                     daily dose (1/3 at 24 o'clock)
 
The patient who is regularly on dialysis, one dose of drug is applied
after each session of a hemodialysis.

Features of use:

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.
Treatment needs to be continued before emergence of kliniko-hematologic remission. The premature termination of treatment leads to a recurrence.
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 with 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.
Allergic reactions meet at patients with intolerance of acetylsalicylic acid more often.
Influence of medicine for a medical use on ability to manage vehicles and mechanisms: Does not exert impact on ability to driving and other mechanisms. However it is necessary to take possibility of dizziness and spasms into account.

Side effects:

From the alimentary system: a loss of appetite, taste change, an abdominal pain, nausea, vomiting, diarrhea, a meteorism, abdominal pains, an abnormal liver function (jaundice, hepatitis, гепатонекроз, a hyperbilirubinemia, increase in activity of alaninaminotranspherases (ALT), aspartate aminotransferases (nuclear heating plant), increase in activity of the alkaline phosphatase (AP), a hepatocellular necrosis), including with a lethal outcome.

From a nervous system: headache, dizziness, excessive fatigue, spasms.

From bodies of a hemopoiesis: leukopenia, thrombocytopenia

(bleedings, petechias), neutropenia, agranulocytosis.

From cardiovascular system: increase in duration of an interval of QT, blinking/trembling of ventricles.
Allergic reactions: skin rash, multiformny exudative erythema (including 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 several or higher doses of drug along with other medicines the following medicinal interactions are possible:
At use of a flukonazol with warfarin the prothrombin time increases (on average by 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
flukonazol and peroral hypoglycemic means at patients with a diabetes mellitus
it is allowed, however the doctor has to mean a possibility of development of a hypoglycemia.
Simultaneous use of a flukonazol and Phenytoinum can bring to
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 concentration of drug within a therapeutic interval.
The combination with rifampicin leads to decrease in the area under a curve "concentration time" (AUC) for 25% and to 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 control concentration of cyclosporine in blood at the patients receiving флуконазол as at use of a flukonazol and cyclosporine for 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.
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 as reception of a flukonazol leads to decrease in average speed of clearance of theophylline from plasma.
At simultaneous use of a flukonazol, terfenadin and tsizaprid cases of undesirable reactions from heart are described, including paroxysms of ventricular tachycardia (torsades des points).
Simultaneous use of a flukonazol and hydrochlorothiazide can lead to increase of concentration of a flukonazol in a blood plasma for 40%.
There are messages on interaction of the flukonazol and a rifabutin which was followed by increase in serumal concentration of the last. At simultaneous use of a flukonazol and rifambutin 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.
Increases concentration of midazolam in this connection the risk of development of psychomotor effects increases (it is more expressed at use of a flukonazol inside, than intravenously).
Increases concentration of a takrolimus in this connection the risk of nephrotoxic action increases.
The single dose of a flukonazol at treatment of vulval candidiasis is not followed by significant interactions.

Contraindications:

– hypersensitivity to drug (including to other azolny antifungal medicines in the anamnesis);
– 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 QT interval;
– children's age up to 3 years.
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 potentially gepatotoksichny medicines, 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), a concomitant use of a terfenadin and a flukonazol in a dose less than 400 mg/days, patients with intolerance of acetylsalicylic acid, pregnancy, alcoholism.
Use at pregnancy and in the period of a lactation
Use of drug for pregnant women – is inexpedient, except for severe or life-threatening forms of fungal infections when the potential advantage of use of a flukonazol for mother considerably exceeds possible risk for a fruit.
Flukonazol gets into breast milk in the concentration close to plasma therefore use of drug in the period of a lactation – is contraindicated.

Overdose:

Symptoms: hallucinations, paranoid behavior, spasms.
Treatment: symptomatic, gastric lavage, artificial diuresis. The hemodialysis within 3 hours reduces concentration in plasma approximately by 50%.

Storage conditions:

In the dry place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

Without recipe

Packaging:

Capsules of 50 mg and 150 mg.
On 7 capsules a dosage of 50 mg or on 1 capsule a dosage of 150 mg in bank polymeric. To one bank together with the application instruction in a pack cardboard.