Flukonazol

General characteristics. Structure:

Active agent: флуконазол 50 mg.

Excipients: lactose - 0,08172 g, starch prezhelatinovy - 0,02652g, aerosil (silicon dioxide colloid) - 0,00016 g, sodium паурилсульфат - 0,00016 g, magnesium stearate of-0,00144 g.

Structure of the capsule: dye quinolinic yellow, понсо, azoruby, blue patent (E131), diamond black, titanium dioxide (E171), gelatin.

Active agent: флуконазол 150 mg.

Excipients: lactose - 0,05849 g, starch prezhelatinovy - 0,01898 g, aerosil (silicon dioxide colloid) - 0,00023 g, sodium паурилсульфат - 0,00023 g, magnesium stearate - 0,00207 g

Structure of the capsule: titanium dioxide, gland oxide red, quinolinic yellow, yellow sunset, azoruby, gelatin.

Pharmacological properties:

Pharmacodynamics. Flukonazol, the representative of a class of triazolny antifungal means, is powerful selection inhibitor of synthesis of sterop in a cell of mushrooms.
Drug эфсрективен 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, Coccidiodes immitis and Histoplasma capsulatum is shown.

Pharmacokinetics. After intake флуконаэол it is well soaked up, its bioavailability — 90%. The maximum concentration 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/l. 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 after reception, the elimination half-life of a flukonazol makes about 30 h. 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%.
Flukonaeol well gets into all biological liquids of an organism. 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. Flukonaeol is brought generally by kidneys; about 80% of the entered dose are removed with urine in not changed look. The clearance of a flukonazol is proportional to clearance of creatinine. Metabolites of a flukonazol in perisrerichesky 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 kandidoz:vaginalny 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, a tep, 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:

Inside.
The adult at cryptococcal meningitis and криптококковыч 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 times/days. Treatment duration at cryptococcal invrektion 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 (4 capsules on 50 mg) during a long span.
At a kandidemiya, the disseminated candidiasis and other invasive candidosis infections the dose usually makes 400 mg (8 capsules on 50 mg) in the first days, and then — on 200 mg (4 capsules on 50 mg). At insufficient clinical performance the dose of drug can be increased to 400 mg/days (8 capsules on 50 mg). 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.
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. 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 vaginal candidiasis флуконаэол 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 of 1 times in 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 fluko-naeol appoint once in a dose 150 mg inside.
For prevention of candidiasis the recommended dose of a flukonazol makes 50-400 mg of 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 (8 capsules on 50 mg) 1 time/days Flukonaeol 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 during 2 weeks, some patients need the third dose of 300 mg in week while regarding cases it is sufficient a single dose 300 (2 capsules on 150 mg) — 400 mg (8 capsules on 50 mg); the alternative scheme of treatment is use on 50 mg during 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 according to.
At deep local mycoses use of drug in a dose 200 (4 capsules on 50 mg) — 400 (8 capsules on 50 mg) 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, 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.

Use of capsules of Flukonazol on 50 mg at children from 4 to 15 years

Disease	Age of the child and body weight
	4–6 years the average weight of the child is 15–20 kg	7–9 years the average weight of the child is 21–29 kg	10–12 years the average weight of the child is 30–40 kg	12–15 years the average weight of the child is 40–50 kg
Gullet candidiasis (3 mg/kg/days)	1 капс. 50 mg a day	1–2 капс. 50 mg a day	2 капс. 50 mg once	2–3 капс. 50 mg once
Treatment period	During not less than 3 weeks and during 2 weeks after regression of symptoms
Candidiasis of mucous membranes (3 mg/kg/days)	In the 1st day — 2–3 капс. Further — on 1 капс. / days	In the 1st day — 2–4 капс. Further — on 1–2 капс. / days	In the 1st day — 4–5 капс. Further — 2 капс. / days once	In the 1st day — 5–6 капс. Further — 2–3 капс. / days once
Treatment period	In the first day the shock dose (6 mg/kg/days) for the purpose of more bystry achievement of constant equilibrium concentration is appointed, then treatment is continued during not less than 3 weeks
Generalized candidiasis and cryptococcal infection (including meningitis) (6–12 mg/kg/days)	2–5 капс. / days	2–6 капс. / days	4–7 капс. / days	5–8 капс. / days
Treatment period	During 10–12 weeks (before laboratory confirmation of lack of activators in liquor)
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 (on 3–12 mg/kg/days)	1–5 капс. / days	1–6 капс. / days	2–7 капс. / days	2–8 капс. / days
Treatment period	Drug is appointed in doses, depending on expressiveness and duration of preservation of the induced neutropenia

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. Patients with a renal failure (creatinine Cl less than 50 ml/min.) the mode of dosing should correct, as shown below (tab. 2).
Flukonazol is brought generally with urine in not changed look. At a chronic renal failure the shock dose of 50-400 mg is originally entered. If Cl of creatinine (KK) 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.

Use of drug for patients with renal failures

Clearance of creatinine	Interval / daily dose
> 40 ml/min.	24 h (usual mode of dosing)
21–40 ml/min.	48 h (1 time in 2 days) or a half of a usual daily dose (1/2 in 24 h)
10–20 ml/min.	72 h (1 time in 3 days) or a third of a usual daily dose (1/3 in 24 h)

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.
 
During treatment it is necessary to control blood indicators, function of kidneys and a liver. At emergence of disturbances of functions of kidneys 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.

Side effects:

From the alimentary system: the loss of appetite, taste changes, an abdominal pain, vomiting, nausea, diarrhea, a meteorism, is rare — an abnormal liver function (jaundice, hepatitis, гепатонекроз, a hyperbilirubinemia, increase in activity of alaninaminotranspherase, aspartate aminotransferase, increase in activity of an alkaline phosphatase, a hepatocellular necrosis), including heavy.
 
From a nervous system: a headache, dizziness, excessive fatigue, it is rare — spasms.
 
From bodies of a hemopoiesis: seldom — a leukopenia, thrombocytopenia (bleedings, petechias), a neutropenia, an agranulocytosis.
 
Allergic reactions: skin rash, it is rare — a multiformny exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease), anaphylactoid reactions (including a Quincke's disease, a face edema, a small tortoiseshell, a skin itch).
 
From cardiovascular system: increase in duration of an interval of QT, blinking/trembling of ventricles.
 
Others: seldom — a renal failure, an alopecia, a hypercholesterolemia, a gipertriglitseridemiya, a hypopotassemia.

Interaction with other medicines:

At use of a flukonazol with warfarin PV increases (on average by 12%). In this regard it is recommended to watch carefully PV indicators 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 Flukonazol and peroral hypoglycemic means at patients with diabetes is allowed, however the doctor has to mean a possibility of development of a hypoglycemia.
 
Simultaneous use of 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 Flukonazol's dose.
 
It is recommended to exercise control of concentration of cyclosporine in blood at patients, receiving Flukonazol since use of a flukonazol and cyclosporine for patients with the replaced kidney (Flukonazol's reception 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 since reception of a flukonazol leads to decrease in average speed of clearance of theophylline from plasma.
 
At simultaneous use of a flukonazol with terfenadiny and tsizapridy cases of undesirable reactions from heart are described, including paroxysms of ventricular tachycardia (torsades de points).
 
Simultaneous use of a flukonazol and hydrochlorothiazide can lead to increase of concentration of a flukonazol in plasma for 40%.
 
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 Flukonazol and a 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.
 
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 in/in).
 
Increases concentration of a takrolimus in this connection the risk of nephrotoxic action increases.

Contraindications:

— a concomitant use of a tersrenadin or the astemizol and other drugs extending QT interval.
— hypersensitivity to drug or relatives on structure to azolny connections.
— children's age (up to 3 years).

WITH CARE
Liver and/or renal failure, 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 potentially gepatotoksichny medicines, alcoholism.

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

Overdose:

Symptoms: hallucinations, paranoid behavior.
Treatment: symptomatic — a gastric lavage, an 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 of 15-25 °C. To store in the place, unavailable to children. A drug period of validity - 2 years.

Issue conditions:

Without recipe

Packaging:

Capsules of 50 mg and 150 mg.

On 1, 2, 3, 4, 5, 6, 7 or 10 capsules in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 1, 2, 7, 10, 14 or 28 capsules in a container polymeric or фпакон from glass melt with a screw mouth with the screwed cover. One container (bottle) or 1, 2, 3, 4, 7 blister strip packagings together with the application instruction place in a pack from a cardboard.
On 5,10 or 20 containers (bottles) or on 10, 20, 40, 70, 80 and 100 blister strip packagings together with the corresponding number of the application instruction put in a box from a cardboard (for hospitals).