Flukonazol

General characteristics. Structure:

Active ingredient: 2 mg of a flukonazol in 1 ml.

Flukonazol - antifungal means.

Pharmacological properties:

Pharmacodynamics. Flukonazol - the antifungal means derivative of triazole. 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 a membrane lipid - 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, does not influence concentration of steroids at women of childbearing age.

It is active at opportunistic mycoses, including the caused 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 dermatitidis, Histoplasma capsulatum (including at an immunosuppression).

Strains of Candida crusei and Candida glabrata are less sensitive to a flukonazol, than Candida ablicans. Candida ablicans strains steady against a ketokonazol, rezistentna and to a flukonazol.

Pharmacokinetics. After intravenous administration well gets into all fabrics and liquids of an organism. Concentration of a flukonazol in a blood plasma are in direct proportionality from the entered dose. Level of equilibrium concentration of 90% is reached by 4-5 days (at introduction of 1 times a day). The volume of distribution approaches the total amount of water in an organism. Linkng with proteins of plasma makes 11-12%. Elimination half-life of T1/2-long (about 30 hours). Concentration of active agent in breast milk, joint liquid, saliva, a phlegm and peritoneal liquid are similar to that in plasma. Well gets into cerebrospinal fluid (SMZh), concentration in SMZh reach 50% of concentration in plasma; at fungal meningitis concentration in SMZh makes about 80% of level in plasma. In stalemate liquid, epidermis and a corneous layer the concentration exceeding serumal (the selection accumulation) are reached. The metabolites of a flukonazol circulating in peripheral blood are not found. It is removed preferential by kidneys (80% - in not changed look). About 11% of the entered dose of a flukonazol are removed in the form of metabolites.

The pharmacokinetics of a flukonazol significantly depends on a functional condition of kidneys. T1/2 raises at patients with an impaired renal function - there is inverse relation between an elimination half-life and clearance of creatinine.

At children the following parameters of pharmacokinetics of a flukonazol were revealed. At single intravenous administration in a dose of 3 mg/kg to children at the age of 11 days - 11 months of T1/2 make 23 hours, AUC - 110,1 mkg • ч / ml. At repeated intravenous administration T1/2 is equal to premature children (about 28 weeks of development) 74 hours in the first days with the subsequent reduction in a dose of 6 mg/kg till 53-47 o'clock by 7-13 days, AUC makes 271 mkg • h/ml in the first days with the subsequent increase up to 490-360 mkg • ч / by 7-13 days. At repeated intravenous administration AUC – 41,6 mkg • ч / is equal to ml in a dose of 3 mg/kg to children at the age of 5 years - 15 years of T1/2 15,5 hours.

Indications to use:

Drug is used: at a cryptococcosis, including cryptococcal meningitis and infections of other localization (lungs, skin) patients with a normal immune response and at patients have AIDS, recipients of transplanted organs and patients with other forms of an immunodeficiency; for a maintenance therapy for the purpose of prevention of a recurrence of a cryptococcosis at patients AIDS; at generalized candidiasis, including a kandidemiya, the disseminated candidiasis and other forms of an invasive candidosis infection (an infection of abdominal organs, an endocardium, eyes, respiratory and uric ways) at patients with malignant tumors, sick intensive care units, the patients receiving cytostatic or immunosuppressive means and also in the presence of other factors contributing to development of candidiasis.

Route of administration and doses:

The drug is administered intravenously kapelno. Duration of infusion of 1 bottle (100 ml) has to make not less than 60 minutes at adults and 120 minutes at children.

The adult drug is appointed in the following doses.

At cryptococcal infections, including at cryptococcal meningitis in the first day of treatment appoint 400 mg of drug, then continue treatment in a dose of 200-400 mg of 1 times a day.

At a kandidemiya, the disseminated candidiasis, other invasive candidosis infections in the first day of therapy appoint 400 mg of a flukonazol, then - 200 mg (if necessary - 400 mg) in days. Duration of treatment is defined individually.

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 should correct the mode of dosing of a flukonazol, as shown below. At clearance of a kreatitin more than 50 ml a minute appoint a usual daily dose. At clearance of creatinine less than 50 ml a minute, in case of single administration of drug change of a dose is not required. At patients (including children) with renal failures at repeated administration of drug it is necessary to enter a shock dose from 50 to 400 mg originally. After introduction of a shock dose the daily dose is defined taking into account indications to use and by sizes of clearance of creatinine. At clearance of creatinine of 21-50 ml a minute enter a half of the recommended dose of 1 times at 24 o'clock or a usual dose - 1 time at 48 o'clock. At clearance of creatinine of 10-20 ml a minute enter 1/3 recommended doses of 1 times at 24 o'clock or a usual dose - 1 time at 72 o'clock. The patients who is on a hemodialysis should appoint drug in a standard dose after each session of a hemodialysis.

To children at treatment of generalized candidiasis and cryptococcal infection (including cryptococcal meningitis) the recommended dose makes 6 - 12 mg/kg a day. The drug is administered daily 1 time a day. Flukonazol children should not appoint in a daily dose which would exceed that at adults. At children, as well as at adults, duration of treatment depends on clinical and mycologic effect.

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 transfer of the patient from intravenous administration on reception of capsules or from peroral introduction on intravenous, there is no need to change a daily dose of a flukonazol.

Features of use:

Treatment flukonazoly can be begun in the absence of results of crops or other laboratory researches. After data acquisition of a mycologic research the corresponding correction of fungicidal therapy is recommended.

During treatment it is not recommended to take alcoholic drinks and to accept sedative drugs. Before the temporary termination of treatment leads to a recurrence.

Deterioration in ability to manage car and mechanisms, connected with introduction of a flukonazol, is improbable.

With extra care, on strict medical indications drug is used at a liver and/or renal failure, a concomitant use of potentially gepatotoksichny medicines, alcoholism, at children's age (up to 6 months). For newborn children at the age of less than 2 weeks an interval between administrations of drug - 72 h, to children at the age of 2-4 weeks enter the same dose with an interval of 48 h. At use of a flukonazol for these categories of patients careful medical control is necessary

When developing skin rashes at patients with an immunosuppression careful observation is necessary, and in case of progressing of skin reaction it is necessary to stop treatment (danger of development of a syndrome of Stephens-Johnson, a Lyell's disease).

Control of a prothrombin ratio at simultaneous use with anticoagulants of a coumarinic row is necessary.

It is recommended to exercise control of concentration of cyclosporine in blood at the patients receiving флуконазол.

Side effects:

As a rule, флуконазол it is well transferred.

At drug use in some cases (it is preferential at persons with the weakened immunity) possibly emergence of manifestations of side effect of drug.

From the alimentary system: the loss of appetite, nausea, vomiting, dyspepsia, locks or diarrhea, a meteorism, an abdominal pain, is rare - an abnormal liver function (an ikterichnost of scleras, jaundice, a hyperbilirubinemia, increase in activity of ALT, nuclear heating plant and an alkaline phosphatase).

From a nervous system: a headache, dizziness, fatigue, it is rare - spasms.

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

Allergic reactions: skin rash, it is rare - a multiformny exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease), anaphylactic reactions, a Quincke's disease, a face edema, an itch.

Others: seldom - a renal failure, an alopecia, exfoliative skin diseases, a hypercholesterolemia, a gipertriglitseridemiya, a hypopotassemia, taste change.

Interaction with other medicines:

Drug is compatible from 5%, 10% or 20% glucose solution, Ringer's solution, Hartman's solution, solution of chloride potassium in glucose, solution of sodium of bicarbonate of 4,2%, isotonic solution of sodium of chloride. It is not recommended to mix solution of a flukonazol of 0,2% for infusions with any other drugs.

Rifampicin accelerates metabolism of a flukonazol: reduces an elimination half-life by 20% and AUC - for 25% (dose adjustment of a flukonazol is necessary).

Plasma concentration of a rifabutin increases flukonazoly in this connection the risk of a uveitis in case of their combined use increases (it is necessary to lower a dose of a rifabutin).

Flukonazol extends an elimination half-life and increases concentration in plasma of derivatives of sulphonylurea. Thereof at a concomitant use with sulphonylurea derivatives (Chlorproramidum, Glibenclamidum, глипизид and Tolbutamidum) it is necessary to control periodically concentration of glucose in blood for prevention of development of a hypoglycemia and if it is necessary, to make dose adjustment of gipoglikemiziruyushchy medicines.

Flukonazol increases efficiency of coumarinic anticoagulants (at the patients receiving warfarin in combination with flukonazoly increase in a prothrombin time on average by 12% is noted); in this regard it is necessary to control constantly a prothrombin time at co-administration of a flukonazol with coumarinic anticoagulants.

Flukonazol strengthens pharmacological effect of antihistamines (астемизол, терфенадин); the anxiolytics relating to group of benzodiazepines of the short period of action (at use with midazolam, triazolamy careful observation of the patient for the purpose of the corresponding dose decline of benzodiazepine in case of a neobjodimost is necessary); Phenytoinum (in clinically significant degree; at the combined use control of concentration of Phenytoinum in plasma and correction of its dose is necessary); a zidovudine (increase in side effects of a zidovudine is possible); a takrolimusa (nephrotoxicity cases are described).

Terfenadin and цизаприд increase risk of developing of arrhythmias, including Bouveret's ventricular disease (torsades de pointes); it is necessary to avoid combined use.

Flukonazol, presumably, oppresses cyclosporine metabolism (increases concentration in cyclosporine plasma), strengthens its pharmacological action.

Drug extends an elimination half-life of theophylline and increases risk of development of intoxication (theophylline dose adjustment is necessary).

Multiple dose of a hydrochlorothiazide leads to increase in concentration of a flukonazol in plasma for 40%.

Contraindications:

Hypersensitivity (including to other azolny antifungal drugs in the anamnesis), co-administration with tsizapridy, astemizoly and terfenadiny). Use of a flukonazol at pregnancy is contraindicated, except for cases of heavy, generalized and potentially life-threatening fungal infections when the expected advantage of treatment surpasses potential risk for a fruit or the newborn. Use in the period of a lactation is contraindicated (it is necessary to cancel breastfeeding).

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: artificial diuresis, symptomatic therapy. The hemodialysis during 3 h reduces concentration of a flukonazol in plasma approximately by 50%.

Issue conditions:

According to the recipe

Packaging:

Solution for infusions of 2 mg/ml in bottles of 100 ml.