Дифлазон®

General characteristics. Structure:

Active ingredient: 2,0 mg of a flukonazol.

Excipients: sodium chloride, water for injections.

Antifungal drug of a wide range of antifungal action for intravenous administration.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a class of triazolny antifungal means, is the selection inhibitor of synthesis of sterol in a cell of mushrooms. Drug is active at the mycoses caused by Candida spp. (C. albicans, C. tropicalis), Cryptococcus neoformans, Microsporum spp., Trichoptyton spp., Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum, is less effective against Aspergillus spp. and Penicillium marneffeii is inefficient against C. krusei, C. glabrata, Fussarium spp. and zigomitset.

Pharmacokinetics. After intravenous maintaining флуконазол well gets into fabrics and liquids of an organism. Concentration in a blood plasma is in direct proportionality from a dose. Concentration of active agent in breast milk, joint liquid, saliva, a phlegm and peritoneal liquid is similar that in plasma. In stalemate liquid, epidermis and a corneous layer (the selection accumulation) the concentration exceeding serumal are reached. Well gets into cerebrospinal fluid, at fungal meningitis concentration in cerebrospinal fluid makes about 85 % of that in plasma. About 90 % of equilibrium concentration of a flukonazol in a blood plasma (Css) are reached by 4-5 day. Introduction of the "shock" dose (in the first day) twice exceeding a usual daily dose allows to reach the concentration corresponding to 90 % of Css by second day. The seeming volume of distribution (Vd) approaches the general content of liquid in an organism. Communication with proteins of a blood plasma low – 11-12 %.

Elimination half-life (T1/2) – 30 h. Is CYP2C9 isoenzyme inhibitor in a liver. It is removed, preferential, by kidneys (80 % in not changed look, 11 % - in the form of metabolites). The clearance of a flukonazol is proportional to the clearance of creatinine (CC).

The pharmacokinetics of a flukonazol significantly depends on a functional condition of kidneys, at the same time there is inverse relation between T1/2 and KK. After a hemodialysis, during 3 h, concentration of a flukonazol in a blood plasma decreases by 50 %.

The pharmacokinetics of a flukonazol is similar at intravenous administration and intake that allows to pass easily from one type of use to another.

Indications to use:

System candidiasis at patients with or without neutropenia, including dessiminirovanny candidiasis (including chronic) and other forms of the progressing candidosis infection, such, as peritoneal, endocardial and intratracheal, infections of urinary tract. Flukonazol can be applied at patients with malignant new growths, the patients with the diseases contributing to development of a candidosis infection receiving cytostatics, immunodepressanty at stay in intensive care unit.

Candidiasis of mucous membranes: orofaringealny, ezofagealny; noninvasive infections of lungs, a kandiduriya, superficial and chronic atrophic candidiasis of an oral cavity (including HIV – the infected patients and patients with an immunodeficiency).

Cryptococcosis, including cryptococcal meningitis, sepsis, fungal infections of other bodies (lungs, skin). Flukonazol can be used for treatment and prevention of a cryptococcal infection at patients with AIDS and other forms of an immunodeficiency.

Flukonazol can be applied to prevention of candidiasis at patients before a miyelotransplantation and at the patients suffering from malignant new growths, predisposed to such infections as a result of carried out cytostatic or radiotheraphy.

Route of administration and doses:

Intravenously kapelno. At impossibility of use of the drug Diflazon® inside, its use in the form of solution for infusions is recommended. Speed of intravenous administration should not exceed 200 mg/h (20 mg/min.). As soon as there is possible a drug use inside, the patient needs to be transferred to therapy by the drug Diflazon® in a peroral dosage form. The daily dose should not change. In certain cases in the first day of therapy use of a double daily dose is possible.

Adults:

Disease	Dosage 1 bottle (100 ml) = 200 mg
Candidiasis of mucous membranes (except for genital candidiasis)	50 - 100 mg of 1 times a day
Heavy candidiasis of mucous membranes	100 - 200 mg of 1 times a day
System candidiasis	400 mg in the first day, further on 200 - 400 mg of 1 times a day
Heavy system candidiasis	to 800 mg of 1 times a day
Prevention of candidiasis	50 - 400 mg of 1 times a day
Cryptococcal meningitis	400 mg in the first day, further 200 - 400 mg of 1 times a day
Prevention of cryptococcal meningitis	200 mg of 1 times a day

Duration of therapy of system candidiasis depends on clinical effect. Treatment has to continue, at least, 2 weeks after receiving a negative hemoculture or disappearance of clinical displays of a disease.

Candidiasis of mucous membranes. At the first episode of a disease treatment is continued by 7 – 14 days; Patients have 3 weeks with an immunodeficiency. In extremely hard cases 30-day therapy is necessary.

Cryptococcal meningitis at patients with AIDS it is necessary to treat within 6-8 weeks.

For prevention of candidiasis before a miyelotransplantation and/or before treatment by cytostatics or radiotheraphy at patients with malignant new growths it is necessary to appoint the drug Diflazon® some days before alleged development of a neutropenia and to continue treatment of, at least, 7 more days after the quantity of neutrophils exceeds 1000/mm3.

Children:
At patients with normal function of kidneys at a cryptococcosis, including cryptococcal meningitis, sepsis, fungal infections of other bodies (lungs, skin) appoint 6 - 12 mg/kg of body weight a day before laboratory confirmation of lack of activators in liquor. And for treatment of superficial mycoses apply a dose of 3 - 6 mg/kg a day to prevention of a fungal infection. Depending on the response to therapy, the daily dose can be increased to 12 mg/kg a day within not less than 3 weeks. To children at candidiasis of a gullet appoint 3 mg/kg/days once within not less than 3 weeks and within 2 weeks after regression of symptoms; at candidiasis of mucous membranes - 3 mg/kg/days once within not less than 3 weeks.

For children from 5 to 13 years the maximum daily dose makes 400 mg of a flukonazol.

The dose for newborns has to be younger than 2 weeks same, as well as at children of advanced age, but each 72 hours, and for babies at the age of 2 - 4 weeks – the same dose each 48 hours.

At a renal failure ^{the drug Diflazon®} is used according to the following scheme:

Clearance of creatinine	Interval / daily dose
more than 40 ml/min. 21-40 ml/min. 10-20 ml/min.	24 hours (usual mode of dosing) 48 hours or 1/2 usual daily doses 72 hours or 1/3 usual daily doses

Dose adjustment according to recommendations for adults is necessary for children with a renal failure.

After each session of a hemodialysis 50 mg are required in addition once (some authors recommend 100 - 200 mg). At the patients who are on peritoneal dialysis (long out-patient dialysis) use of 150 mg of a flukonazol on 2 liters of dialyzate at an interval of the 2nd day is recommended.

At patients of advanced age in the absence of renal failures it is necessary to adhere to the usual mode of a drug dosing.

It is necessary to apply with care флуконазол to patients with an abnormal liver function.

Features of use:

The drug Diflazon® should be used with care at patients with a renal failure. The dose of the drug Diflazon® should be adjusted according to clearance of creatinine.

It is necessary to use with care the drug Diflazon® to patients with an abnormal liver function. During therapy flukonazoly it is regularly necessary to control activity of liver enzymes and to watch a condition of the patient (probability of development of toxic effects). At increase in activity of "hepatic" enzymes the positive effect from continuation of therapy has to exceed risk of toxic influence on a liver. The hepatotoxic action of a flukonazol is usually reversible, symptoms disappear after the therapy termination.

At emergence of rash in the patient receiving therapy concerning a superficial fungal infection against the background of drug Diflazon® use, further therapy by this drug has to be stopped.

The drug Diflazon®, at its use in a dose of 400 mg a day daily, can increase considerably concentration of a terfenadin in a blood plasma at simultaneous use. At patients who at the same time apply флуконазол and терфенадин spontaneous cases of emergence of heartbeat, tachycardia, dizziness and a stethalgia, at the same time communication between noted side effects against the background of simultaneous use of these drugs were noted it was not obvious. In view of potential danger of such medicinal interaction, simultaneous use of a terfenadin and flukonazol is not recommended.

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

There is a limited experience of use of a flukonazol for children 6 months therefore treatment by the drug Diflazon® should be carried out only if necessary are younger.

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

Special information. 100 ml of solution for infusions (1 bottle) contain 353.8 mg (15.38 mmol) of sodium. 1 ml of solution for infusions contains 3.538 mg (0.1538) sodium that should be considered to patients who are on a diet with the controlled content of sodium.

At pregnancy use of the drug Diflazon® is not recommended. Use of a flukonazol at life-threatening infections when the potential advantage for mother exceeds possible risk for a fruit is possible. In need of use of the drug Diflazon® in the period of a lactation breastfeeding should be stopped.

 Due to the risk of development of side effects it is necessary to be careful at control of vehicles and work with other technical devices demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Classification of frequency of development of side effects (WHO):

very often   > 1/10

often             from> 1/100 to <1/10

infrequently         from> 1/1000 to <1/100

seldom             from> 1/10000 to <1/1000

very seldom  from <1/10000, including separate messages.

From the alimentary system: often: meteorism, nausea, vomiting, abdominal pain, diarrhea, increase in activity of "hepatic" enzymes, loss of appetite, lock; infrequently: abnormal liver functions (jaundice, a hyperbilirubinemia, increase in activity of an alkaline phosphatase, hepatitis, a hepatocellular necrosis), including with a lethal outcome;

From a nervous system: often: feeling of fatigue, headache, dizziness; infrequently: spasms;

From integuments: often: skin rash; infrequently: alopecia; seldom: face edema, urticaria, skin itch, multiformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis (scalded skin syndrome);

From immune system: seldom: anaphylaxis and Quincke's disease;

From system of a hemopoiesis: seldom: leukopenia, thrombocytopenia, neutropenia, agranulocytosis;

From cardiovascular system: infrequently: lengthening of an interval of QT, arrhythmia like "pirouette";

Others: seldom: renal failures, hypercholesterolemia, hypopotassemia, gipertriglitseridemiya.

Interaction with other medicines:

• Simultaneous use of a terfenadin, tsizaprid, astemizol, Pimozidum and quinidine causes increase in concentration of these drugs in a blood plasma that can lead to lengthening of an interval of QT and disturbances of a heart rhythm (torsade de pointes, arrhythmia like "pirouette") in this connection, simultaneous use of these drugs is contraindicated.

• At the patients accepting at the same time warfarin lengthening of a prothrombin time is noted.

• Flukonazol extends Т½ hypoglycemic means for intake and derivatives of a sulfonmochevina (Chlorproramidum, Glibenclamidum, глипизид and Tolbutamidum). These drugs can be used in combination with flukonazoly, but it is necessary to consider probability of development of a hypoglycemia.

• It must be kept in mind that at simultaneous use of Hydrochlorthiazidum and flukonazol, concentration of the last in a blood plasma can increase.

• Rifampicin accelerates metabolism of a flukonazol therefore, it is necessary to increase carefully a dose of a flukonazol at simultaneous use with rifampicin.

• At patients after transplantation of a kidney флуконазол can increase concentration of cyclosporine in a blood plasma therefore, it is necessary to control it.

• Flukonazol increases concentration of theophylline, it is necessary to control concentration of the last.

• Flukonazol can increase concentration of an indinavir or midazolam that can increase risk of development of psychomotor effects (it is more expressed at use of a flukonazol inside, than in/in) therefore, the adequate dose decline of these drugs is necessary.

• The combined use of a flukonazol and zidovudine can lead to increase in concentration of a zidovudine in a blood plasma which AUC increases.

Flukonazol in a dose of 50-200 mg has no significant effect on efficiency of the peroral combined contraceptives.

There are messages on medicinal interaction at use of a flukonazol in combination with rifabutiny that leads to increase in concentration of the last in a blood plasma. The patients receiving at the same time рифабутин and флуконазол have to be under observation of the doctor.

• Simultaneous use of a flukonazol and Phenytoinum can increase concentration of Phenytoinum clinically significantly. In need of use of both drugs, it is necessary to control concentration and to adjust Phenytoinum dose to therapeutic concentration.

• There are messages about medicinal interaction at use of a flukonazol and takrolimus that leads to increase in concentration of a takrolimus in a blood plasma. The patients receiving at the same time такролимус and флуконазол have messages on nephrotoxicity. The patients who are at the same time applying такролимус and флуконазол have to be under observation of the doctor.

Contraindications:

Hypersensitivity to the flukonazol, azolny connections and other ingredients which are a part of drug; the inborn or revealed lengthening of an interval of QT on the electrocardiogram, a concomitant use of the drugs extending QT interval (including antiarrhytmic means of IA and the III classes), pregnancy, the breastfeeding period, simultaneous use of a flukonazol with tsisapridy, terfenadiny (against the background of constant reception of a flukonazol in a dose of 400 mg/days and more), astemizoly, Pimozidum and quinidine.

With care: alcoholism, an achlorhydria and a hypochlorhydria, children's age up to 6 months (safety and efficiency of use are not established), a liver failure, emergence of rash against the background of use of a flukonazol for patients with a superficial fungal infection and invasive/system fungal infections, simultaneous use of a terfenadin and 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, simultaneous use of the medicines causing arrhythmias).

Overdose:

The most frequent symptoms of overdose are nausea, vomiting, diarrhea and in more hard cases - spasms, hallucinations.

Treatment: symptomatic. As флуконазол it is removed, generally by kidneys, the artificial diuresis accelerates its removal. Carrying out a three-hour hemodialysis reduces concentration of a flukonazol in a blood plasma by a half.

Storage conditions:

To store at a temperature not above 25 °C, in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for infusions, 2 mg/ml. On 100 ml of drug place in a bottle from colourless glass (type I, Ph.Eur.) with the rubber bung which is pressed out by an aluminum cap and a color plastic protective cover. Apply the internal production code of drug on an aluminum cap. On 1 bottle place in a pack cardboard together with the application instruction.