Дифлюкан®

General characteristics. Structure:

Active agent: флуконазол 50 mg, 100 mg or 150 mg, respectively; excipients: mg lactose 49,708/99,415 / 149,123, corn starch 16,5/33/49,5 of mg, silicon dioxide of colloid 0,117/0,235/0,352 mg, magnesium stearate 1,058/2,115/3,173 of mg, sodium mg lauryl sulfate 0,117/0,235/0,352;

Structure of the capsule (for a dosage of 50 mg): a capsule lid (titanium dioxide (E171) of 1,47%, gelatin to 100%, dye blue patent (Е 131) 0,03%; the capsule case (titanium dioxide (E171) of 3%, gelatin to 100%;

Structure of the capsule (for a dosage of 100 mg): (titanium dioxide (E171) of 3%, gelatin to 100%, Structure of the capsule (for a dosage of 150 mg): (titanium dioxide (E171) of 1,47%, gelatin to 100%, dye blue patent (Е 131) 0,03%; The Structure blackened: shellakovy glaze of 63%, black iron oxide (E172) of 25%, N-butyl alcohol of 8,995%, SHOUTING industrial metilirovanny alcohol 74 of 2%, soy lecithin of 1%, antifoam component DC of 1510 - 0,005%.

Pharmacological properties:

Pharmacodynamics. Flukonazol, triazolny antifungal means, is powerful selection inhibitor of synthesis of sterol in a cell of mushrooms. At intake and intravenous administration флуконазол showed activity on various models of fungal infections at animals. Activity of drug at the opportunistic mycoses including caused by Candida spp is shown., including generalized candidiasis at animals with the suppressed immunity; Cryptococcus neoformans, including intracranial infections; Microsporum spp. and Trychoptyton spp. Also activity of a flukonazol on models of local mycoses at animals, including the infections caused by Blastomyces dermatitides, Coccidioides immitis including intracranial infections, and Histoplasma capsulatum at animals with the normal and suppressed immunity is established. There were messages on cases of the superinfection caused by strains of Candida, other than Candida albicans, which often have natural resistance to a flukonazol (for example Candida krusei). In similar cases alternative antifungal therapy can be required. Flukonazol has high specificity concerning the fungal enzymes dependent on cytochrome P - 450. Therapy flukonazoly in a dose of 50 mg/days during up to 28 days does not influence concentration of testosterone in plasma at men or concentration of steroids at women of childbearing age. Flukonazol in a dose of 200-400 mg/days does not exert clinically significant impact on levels of endogenous steroids and their reaction to stimulation of AKTG at healthy male volunteers. Single or multiple dose of a flukonazol in a dose of 50 mg does not influence metabolism of antipyrine at their concomitant use.

Pharmacokinetics. The pharmacokinetics of a flukonazol is similar at intravenous administration and intake. After intake флуконазол it is well soaked up, its levels in plasma (and the general bioavailability) exceed 90% of those at intravenous administration. The concomitant use of food does not influence absorption of drug at intake. Concentration in plasma reaches peak in 0,5-1,5 h after reception of a flukonazol on an empty stomach, and the elimination half-life makes about 30 h. Concentration in plasma is proportional to a dose. 90% of equilibrium concentration are reached by 4-5th day after the beginning of therapy (at multiple dose of drug once a day).
Introduction of the shock dose (in the 1st day) twice exceeding a usual daily dose does possible achievement of equilibrium 90% of concentration by 2nd day. The volume of distribution approaches the general content of water in an organism. Linkng with proteins - low (11-12%).
Flukonazol well gets into all liquids of an organism. Concentration of a flukonazol in saliva and a phlegm are similar to its concentration in plasma. At patients with fungal meningitis of concentration of a flukonazol in cerebrospinal fluid make about 80% of its concentration in plasma.
In a corneous layer, epidermis derma and stalemate liquid high concentration which exceed serumal are reached. Flukonazol collects in a corneous layer. At reception in a dose of 50 mg once a day concentration of a flukonazol in 12 days makes 73 mkg/g, and in 7 days after the treatment termination – only 5,8 mkg/g. At use in a dose of 150 mg once a week concentration of a flukonazol in a corneous layer for the 7th day makes 23,4 mkg/g, and in 7 days after reception of the second dose - 7,1 mkg/g.
Concentration of a flukonazol in nails after 4-month use in a dose of 150 mg once a week makes 4,05 mkg/g in healthy and 1,8 mkg/g in the affected nails; in 6 months after completion of therapy флуконазол is still defined in nails.
Drug is removed, generally by kidneys; about 80% of the entered dose are found in urine in not changed look. The clearance of a flukonazol is proportional to clearance of creatinine. The circulating metabolites are not found.
Long plasma elimination half-life allows to accept флуконазол once at vaginal candidiasis and once a day or once a week - at other indications.
When comparing concentration in saliva and plasma after a single dose of 100 mg of a flukonazol in the form of the capsule and suspension (rinsing, preservation in a mouth within 2 min. and a proglatyvaniye) it is established that the maximum concentration of a flukonazol in saliva at reception of suspension was observed in 5 min. after inclusion and in 182 times exceeded that after reception of the capsule (it was reached in 4 hours). Approximately in 4 hours of concentration of a flukonazol in saliva were identical. Average area under curve AUC (0-96) in saliva was much higher at suspension reception, than capsules. Essential distinctions of speed of removal from saliva or indicators of pharmacokinetics in plasma when using two dosage forms are not revealed.

Pharmacokinetics at children
At children the following pharmacokinetic parameters were received:
Age the Dose (mg/kg) the Period of a poluvyve-deniye (hour) the Area under a curve (¼¬ú.þ/ml)
11 days – 11 months Oncein/in 3mg/kg  23 110.1
9 months - 13 years Single inside 2mg/kg  25.0 94.7
9 months - 13 years Single inside 8mg/kg  19.5 362.5
5 years – 15 years Repeatedlyin/in 2mg/kg 17.4 * 67.4 *
5 years – 15 years Repeatedlyin/in 4mg/kg 15.2 * 139.1 *
5 years – 15 years Repeated in/in 8mg/kg 17.6 * 196.7 *
Middle age
7 years Repeated inside 3mg/kg  15.5 41.6
* the indicator noted in the last day 

To premature children (about 28 weeks of development) флуконазол entered intravenously in a dose 6 mg/kg every 3rd day before introduction of at most 5 doses at that time while children remained in intensive care unit. The average elimination half-life made 74 h (within 44-185 h) in the 1st day, with reduction for the 7th day on average to 53 h (within 30-131 h) and for the 13th day on average to 47 h (within 27-68 h).
Znacheniya Square under a curve made 271 ¼¬ú.þ/ml (within 173-385 ¼¬ú.þ/ml) in
The 1st day, then increased to 490 ¼¬ú.þ/ml (within 292-734 ¼¬ú.þ/ml) for the 7th day and decreased on average to 360 ¼¬ú.þ/ml (within 167-566 ¼¬ú.þ/ml) by 13th day.
The volume of distribution made 1183 ml/kg (within 1070-1470 ml/kg) in the 1st day, then increased on average to 1184 ml/kg (within 510-2130 ml/kg) for the 7th day and to 1328 ml/kg (within 1040-1680 ml/kg) for the 13th day.
Pharmacokinetics at elderly patients
At single use of a flukonazol in a dose of 50 mg inside to elderly patients at the age of 65 years is also more senior some of which at the same time accepted diuretics, it is established that the maximum concentration in Cmax plasma was reached in 1,3 hours after reception and made 1,54 mkg/ml, average AUC values - 76,4 ± 20,3 ¼¬ú.þ/ml, and an average elimination half-life – 46,2 h. Values of these pharmacokinetic parameters are higher, than at young patients. The concomitant use of diuretics did not cause the expressed change of AUC and Cmax. The clearance of creatinine (74 ml/min.), percent of the drug removed with urine in an invariable look (than 0 - 24 h, 22%) and renal clearance of a flukonazol (0,124 ml / ¼¿¡./kg) at elderly patients is lower in comparison with young people. Higher values of pharmacokinetic parameters at the elderly patients accepting флуконазол probably are connected with the lowered renal function characteristic of advanced age.

Indications to use:

- a cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), including at patients with a normal immune response and patients with AIDS, recipients of transplanted organs and patients with other forms of an immunodeficiency; a maintenance therapy for the purpose of prevention of a recurrence of a cryptococcosis at patients with AIDS;

- generalized candidiasis, including a kandidemiya, the disseminated candidiasis and other forms of an invasive candidosis infection, such as infections of a peritoneum, endocardium, eyes, respiratory and uric ways, including at the patients with malignant tumors who are in intensive care units and receiving cytotoxic or immunosuppressive means and also at patients with other factors contributing to development of candidiasis;

- candidiasis of mucous membranes, including mucous oral cavities and drinks, a gullet, noninvasive bronchopulmonary infections, a kandiduriya, the skin and mucous and chronic atrophic candidiasis of an oral cavity (connected with carrying dentures), including at patients with the normal and suppressed immune function; prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS;

- genital candidiasis; acute or recurrent vaginal candidiasis; prevention 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 the patients with malignant tumors predisposed to such infections as a result of cytotoxic chemotherapy or radiation therapy;

- skin mycoses, including mycoses of feet, bodies, inguinal area, a chromophytosis, an onychomycosis and skin candidosis infections;

- deep local mycoses at patients with normal immunity, a coccidioidomycosis, a paracoccidioidomycosis, a sporotrichosis and histoplasmosis.

Route of administration and doses:

Capsules: inside. Capsules are swallowed entirely.
Suspension: inside.
Instruction for suspension preparation: with powder for preparation of suspension to add 24 ml of water to contents of one bottle and to shake up carefully. Before each use to shake up.
Solution for intravenous administration: intravenous infusions.

Therapy can be begun before obtaining results of crops and other laboratory researches. However anti-infectious therapy needs to be changed as appropriate when results of these researches become known.
Flukonazol it is possible to accept inside or to enter intravenously by infusion with a speed no more than 10 ml/min.; the choice of a way of introduction depends on a clinical condition of the patient. At transfer of the patient from drug, intravenous on oral administration, or on the contrary change of a daily dose it is not required. In solution for intravenous administration флуконазол chloride sodium solution is included in 0,9%; in each 200 mg (a bottle on 100 ml) about 15 mmol of Na + and Cl-contain. Therefore at patients who need restriction of consumption of sodium or liquid it is necessary to consider liquid rate of administering.
The daily dose of Diflyukana® depends on character and weight of a fungal infection. At vaginal candidiasis the single dose of drug is in most cases effective. At the infections demanding repeated reception of antifungal drug, treatment should be continued before disappearance of clinical or laboratory signs of an active fungal infection. Sick AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis the maintenance therapy is usually necessary for prevention of a recurrence of an infection.
Use for adults
1. At cryptococcal meningitis and cryptococcal infections of other localization in the first day usually appoint 400 mg, and then continue treatment in a dose of 200-400 mg once a day. Duration of treatment of cryptococcal infections depends on existence of clinical and mycologic effect; at cryptococcal meningitis treatment is usually continued at least by 6-8 weeks.
For prevention of a recurrence of a cryptococcal meninigit at patients with AIDS, after end of a full course of primary treatment, therapy of Diflyukanom® in a dose of 200 mg/days can be continued during very long term.
2. At a kandidemiya, the disseminated candidiasis and other invasive candidosis infections the dose usually makes 400 mg in the first day, then on 200 mg/days. Depending on expressiveness of clinical effect the dose can be increased to 400 mg/days. Duration of therapy depends on clinical performance.
3. At oropharyngeal candidiasis drug is usually appointed on 50-100 mg within 7-14 days once a day. If necessary, patients with the expressed suppression of immune function can continue treatment during longer time. At the atrophic oral candidiasis connected with carrying dentures, drug usually appoint in a dose 50 mg within 14 days in combination with local antiseptic agents for processing of a prosthesis once a day.
At other candidosis infections of mucous membranes (except for genital candidiasis, see below), for example, an esophagitis, noninvasive bronchopulmonary infections, 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 with AIDS after end of a full course of primary therapy of Diflyukan® about 150 mg once a week can be appointed.
4. At vaginal candidiasis of Diflyukan® appoint once inside in a dose 150 mg.
For decrease in frequency of a recurrence of vaginal candidiasis it is possible to use drug in a dose 150 mg once a month. Duration of therapy is determined individually; it varies from 4 to 12 months. More frequent use of drug can be required by some patients. Use of a single dose to children is younger than 18 years and to patients 60 years without doctor's instructions are more senior it is not recommended.
At the balanitis caused by Candida, Diflyukan® appoint once in a dose 150 mg inside.
5. For prevention of candidiasis the recommended dose of Diflyukana® makes 50-400 mg depending on a risk degree of development of a fungal infection once a day. For patients with high risk of a generalized infection, for example, from expressed or it is long the remaining neutropenia, the recommended dose makes 400 mg once a day. Дифлюкан® appoint some days before the expected development of a neutropenia and, after increase in number of neutrophils more than 1000 in mm3, treatment is continued by 7 more days.
6. At skin infections, including mycoses of feet, smooth skin, inguinal area and at candidosis infections, the recommended dose makes 150 mg once a week or 50 mg once a day. Therapy duration usually makes 2-4 weeks, however at mycoses of feet longer therapy can be required (up to 6 weeks).
At a chromophytosis the recommended dose makes 300 mg once a week within 2 weeks; some patients need the third dose of 300 mg a week while for some patients it is accorded rather single welcome of 300-400 mg. The alternative scheme of treatment is use of drug on 50 mg within 2-4 weeks once a day.
At tinea unguium (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 usually requires 3-6 months and 6-12 months according to. However growth rate can vary over a wide range at different people, and also depending on age. After successful treatment it is long the remaining persistent infections sometimes change of a shape of nails is observed.
7. 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 makes 11-24 months at a coccidioidomycosis, 2-17 months - at a paracoccidioidomycosis, 1-16 months - at a sporotrichosis and 3-17 months - at histoplasmosis.
Use for children
As well as at similar infections at adults, duration of treatment depends on clinical and mycologic effect. For children the daily dose of drug should not exceed that for adults. Дифлюкан® apply daily once a day.
At candidiasis of mucous membranes the recommended dose of Diflyukana® makes 3 mg/kg/days. In the first day for the purpose of more bystry achievement of constant equilibrium concentration the shock dose of 6 mg/kg can be appointed.
For treatment of generalized candidiasis and a cryptococcal infection the recommended dose makes 6-12 mg/kg/days depending on disease severity.
For prevention of fungal infections at patients with the suppressed 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 (see a dosage for adults; for children with a renal failure - see a dosage for patients with a renal failure).
Use for children at the age of 4 weeks and less
At newborns флуконазол it is removed slowly. In the first 2 weeks of life drug is appointed in the same dose (in mg/kg), as to children of more advanced age, but with an interval of 72 h. To children at the age of 3 and 4 weeks the same dose is entered with an interval of 48 h.
Use for elderly people
In the absence of symptoms of a renal failure drug is appointed in a usual dose. The patient with a renal failure (clearance of creatinine <50 ml/min.) the dose of drug is adjusted as it is described below.
Use for patients with a renal failure
Flukonazol is brought, generally with urine in not changed look. At a single dose of change of a dose it is not required. At patients (including children) with a renal failure at repeated use of drug it is necessary to enter originally a shock dose from 50 mg to 400 mg then the daily dose (depending on the indication) is established according to the following table:
Clearance of creatinine (ml/min.) Percent of the recommended dose
> 50
≤ 50 (without dialysis)
Regular dialysis of 100%
50%
100% after each dialysis

Features of use:

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 using a flukonazol their explicit dependence on the general daily dose of drug, duration of therapy, gender and age of the patient is noted. The hepatotoxic action of drug usually was reversible; its signs disappeared after the therapy termination. Patients at whom during treatment drug breaks indicators of function of a liver need to be observed for the purpose of identification of signs of more serious damage of a liver. At emergence of clinical signs or symptoms of damage of a liver which can be connected using a flukonazol drug should be cancelled.
As well as at use of other azoles, флуконазол in rare instances can cause anaphylactic reactions.
During treatment flukonazoly at patients exfoliative skin reactions, such as Stephens-Johnson's syndrome and a toxic epidermal necrolysis in rare instances developed. Patients with AIDS are more inclined to development of heavy skin reactions at use of many drugs. At emergence in the patient during treatment of a superficial fungal infection of rash which can be connected using a flukonazol drug should be cancelled. At emergence of rash in patients with their invasive/system fungal infections it is necessary to observe and cancel carefully drug at emergence of violent defeats or a mnogoformny erythema.
Simultaneous use of a flukonazol in doses less than 400 mg/days and a terfenadina should be carried out under careful control (see the section "Interaction with Other Drugs and Other Forms of Interaction").
As well as other azoles, флуконазол increase in an interval of QT at an ECG can cause. At use of a flukonazol increase in an interval of QT and blinking/trembling of ventricles noted very seldom at seriously sick with multiple factors of risk, such as organic heart diseases, disturbances of electrolytic balance and the accompanying therapy promoting development of similar disturbances. Therefore such patients with potentially pro-arhythmic states should apply флуконазол with care.
Patients with diseases of a liver, heart and kidneys before use of drug are recommended to consult with the doctor. At use of Дифлюкана® 150 mg concerning vaginal candidiasis patients have to be warned that improvement of symptoms is usually observed in 24 h, but their total disappearance sometimes requires several days. At preservation of symptoms within several days, it is necessary to see a doctor.
Дифлюкан® - solution for intravenous administration is compatible to the following solutions:
- 20% glucose solution
- Ringer's solution
- Hartmann's solution
- chloride potassium solution in glucose
- 4,2% bicarbonate sodium solution
- аминофузин
- isotonic normal saline solution.

Дифлюкан® it is possible to enter into infusional system together with one of the listed above solutions. Though cases of specific incompatibility of a flukonazol with other means are not described, nevertheless, it is not recommended to mix it with any other drugs before infusion.

Influence on ability to drive the car and to use the equipment
Experience of use of Diflyukana® demonstrates that disturbance of ability to drive the car and mechanisms connected using drug, a little possibly.

Side effects:

Portability of drug usually very good.
Most often in clinical and post-marketing (*) the researches Diflyukana® noted the following side reactions:
From the central and peripheral nervous system: headache, dizziness *, spasms *, change вкуса*.
From a digestive tract: abdominal pain, diarrhea, meteorism, nausea, dyspepsia *, рвота*.
From a liver: a hepatotoxic, including exceptional cases with a lethal outcome, increase in level of an alkaline phosphatase, bilirubin, serumal level of aminotransferases (ALT and nuclear heating plant), an abnormal liver function *, hepatitis *, a hepatocellular necrosis *, желтуха*.
From skin and hypodermic fabrics: rash, an alopecia *, exfoliative skin diseases *, including Stephens-Johnson's syndrome and a toxic necrolysis of epidermis.
From system of a hemopoiesis and lymphatic системы*: a leukopenia, including a neutropenia and an agranulocytosis, thrombocytopenia.
From an immune sistemy*: an anaphylaxis (including a Quincke's disease, a face edema, urticaria, an itch).
From a cardiovascular sistemy*: increase in an interval of QT at an ECG, blinking/trembling of ventricles (see the section "Special Instructions").
Metabolic/trophic нарушения*: increase in level of cholesterol and triglycerides in plasma, a hypopotassemia.
At some patients who especially have serious diseases, such as AIDS or cancer at treatment of Diflyukanom® and similar drugs changes of indicators of blood, function of kidneys and a liver were observed (see the Section "Special Instructions"), however clinical value of these changes and their communication with treatment are not established.

Interaction with other medicines:

Anticoagulants: as well as other antifungal means – derivatives of an azol, флуконазол, at simultaneous use with warfarin, the prothrombin time (for 12%) raises in this connection development of bleedings is possible (hematomas, bleedings from a nose and digestive tract, a hamaturia, a melena). At the patients receiving coumarinic anticoagulants it is necessary to control a prothrombin time constantly.
Azithromycin: at simultaneous use in a flukonazol in a single dose of 800 mg with azithromycin in a single dose of 1200 mg of the expressed pharmacokinetic interaction between both drugs it is not established.
Benzodiazepines (short action): after midazolam intake, флуконазол significantly increases concentration of midazolam and psychomotor effects, and this influence is more expressed after reception of a flukonazol inside, than at its use intravenously. In need of the accompanying therapy by benzodiazepines of the patients accepting флуконазол it is necessary to observe for the purpose of the corresponding dose decline of benzodiazepine.
Tsizaprid: at simultaneous use of a flukonazol and tsizaprid undesirable reactions from heart are possible, including blinking/trembling of ventricles (torsade de pointes). Use of a flukonazol in a dose of 200 mg of 1 times a day and a tsizaprid in a dose of 20 mg 4 times a day leads to the expressed increase in plasma concentration of a tsizaprid and increase in an interval of QT at an ECG. The concomitant use of a tsizaprid and a flukonazol is contraindicated.
Cyclosporine: at patients with a transplantirovanny kidney, use of a flukonazol in a dose of 200 mg/days leads to slow increase in concentration of cyclosporine. However, at multiple dose of a flukonazol in a dose of 100 mg/days of change of concentration of cyclosporine at recipients of marrow it was not observed. At simultaneous use of a flukonazol and cyclosporine it is recommended to monitorirovat concentration of cyclosporine in blood.
Hydrochlorthiazidum: repeated use of Hydrochlorthiazidum along with flukonazoly leads to increase in concentration of a flukonazol in plasma for 40%. The effect of such degree of manifestation does not demand change of the mode of dosing of a flukonazol from the patients receiving at the same time diuretics, however the doctor should consider it. 
Oral contraceptives: at simultaneous use of the combined oral contraceptive with flukonazoly in a dose of 50 mg of significant effect on the level of hormones it is not established whereas at daily reception of 200 mg of a flukonazol of AUC ethinylestradiol and levonorgestrel increase by 40% and 24% respectively, and at reception of 300 mg of a flukonazol weekly - AUC ethinylestradiol and norethindrone increase for 24% and 13% respectively. Thus, repeated use of a flukonazol in the specified doses can hardly exert impact on efficiency of the combined peroral contraceptive.
Phenytoinum: simultaneous use of a flukonazol and Phenytoinum can be followed by clinically significant increase in concentration of Phenytoinum. In case of need simultaneous use of both drugs it is necessary to control concentration of Phenytoinum and as appropriate to correct its dose for the purpose of ensuring therapeutic concentration in serum.
Rifabutin: simultaneous use of a flukonazol and rifabutin can lead to increase in serumal concentration of the last. At simultaneous use of a flukonazol and rifabutin uveitis cases are described. The patients who are at the same time receiving рифабутин and флуконазол need to be observed carefully.
Rifampicin: simultaneous use of a flukonazol and rifampicin leads to decrease in AUC by 25% and duration of an elimination half-life of a flukonazol for 20%. At the patients who are at the same time accepting rifampicin it is necessary to consider expediency of increase in a dose of a flukonazol.
Sulphonylurea drugs: флуконазол, at a concomitant use, leads to increase in an elimination half-life of peroral drugs of sulphonylurea (Chlorproramidum, Glibenclamidum, a glipizid and Tolbutamidum). A sick diabetes mellitus it is possible to appoint combined use of a flukonazol and peroral drugs of sulphonylurea, but at the same time it is necessary to consider a possibility of development of a hypoglycemia.
Takrolimus: simultaneous use of a flukonazol and takrolimus leads to increase in serumal concentration of the last. Nephrotoxicity cases are described. The patients who are at the same time accepting такролимус and флуконазол should be observed carefully.
Terfenadin: at simultaneous use of azolny antifungal means and a terfenadina developing of serious arrhythmias as a result of increase in an interval of QT is possible. At reception of a flukonazol in a dose of 200 mg/days of increase in an interval of QT it is not established, however, use of a flukonazol in doses of 400 mg/days and causes significant increase in concentration of a terfenadin in plasma above. The concomitant use of a flukonazol in doses of 400 mg/days and more with terfenadiny is contraindicated (see the section "Contraindications"). Treatment flukonazoly in doses less than 400 mg/days in combination with terfenadiny should be carried out under careful control.
Theophylline: at simultaneous use with flukonazoly in a dose of 200 mg within 14 days the average speed of plasma clearance of theophylline decreases by 18%. At purpose of a flukonazol the patient accepting theophylline in high doses or the patient with the increased risk of development of toxic effect of theophylline, it is necessary to watch emergence of symptoms of overdose of theophylline and, if necessary, to correct therapy as appropriate.
Zidovudine: at simultaneous use with flukonazoly increase in concentration of a zidovudine which is probably caused by decrease in metabolism of the last to its main metabolite is noted. Before therapy using a flukonazol in a dose of 200 mg/days within 15 days sick AIDS and ARC (the complex connected with AIDS) established significant increase in AUC of a zidovudine (20%).
At use each 8 hours within 7 days in combination with flukonazoly in a dose of 400 mg/days or without it at an interval of 21 days between two schemes, substantial increase of AUC of a zidovudine (74%) at simultaneous use with flukonazoly is established to HIV-positive patients of a zidovudine in a dose of 200 mg. The patients receiving such combination should be observed for the purpose of identification of side effects of a zidovudine.
Simultaneous use of a flukonazol with astemizoly or other drugs which metabolism is carried out by system of P450 cytochrome can be followed by increase in serumal concentration of these means. At co-administration of a flukonazol, in case of lack of reliable information, it is necessary to be careful. Patients should be observed carefully.
Researches of interaction of peroral forms of a flukonazol at its concomitant use with food, Cimetidinum, antacids, and also after total body irradiation for preparation for bone marrow transplantation showed that these factors do not exert clinically significant impact on absorption of a flukonazol.
The listed interactions are established at repeated use of a flukonazol; interactions with medicines as a result of a single dose of a flukonazol are not known.
Doctors should consider that interaction with other medicines specially was not studied, but it is possible.

Contraindications:

Hypersensitivity to a flukonazol, other components of drug or azolny substances with similar to a flukonazol structure; a concomitant use of a terfenadin during repeated use of a flukonazol in a dose of 400 mg/days and more (see the section "Interaction with Other Drugs and Other Forms of Interaction"); simultaneous use of a tsizaprid (see the section "Interaction with Other Drugs and Other Forms of Interaction").

With care. Disturbance of indicators of function of a liver against the background of use of a flukonazol; 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 pro-arhythmic states at patients with multiple factors of risk (organic heart diseases, disturbances of electrolytic balance and the accompanying therapy promoting development of similar disturbances). Pregnancy and lactation Adequate and controlled researches of pregnant women were not conducted. Cases of multiple inborn defects at newborns whose mothers within 3 and more months received therapy flukonazoly in a high dose (400-800 mg/days) concerning a coccidioidomycosis are described. Communication between these disturbances and reception of a flukonazol is not established. During pregnancy use of a flukonazol it is necessary to avoid, except for hard cases and potentially life-threatening fungal infections when the expected advantage of treatment exceeds possible risk for a fruit. Therefore women of childbearing age should use contraceptives. Flukonazol is found in breast milk in the concentration close to plasma therefore its appointment is not recommended to women in the period of a lactation.

Overdose:

There are messages on overdose of a flukonazol, and in one case for the 42-year-old patient infected with a human immunodeficiency virus, after reception of 8200 mg of drug hallucinations and paranoid behavior developed. The patient was hospitalized; its state was normalized within 48 hours.
In case of overdose the adequate effect can give a symptomatic treatment (including the supporting measures and a gastric lavage).
Flukonazol is brought, generally with urine therefore the artificial diuresis can probably accelerate drug removal. The session of a hemodialysis lasting 3 h reduces the level of a flukonazol in plasma approximately by 50%.

Storage conditions:

Period of validity
- Capsules: 5 years.
- Solution for intravenous administration: 5 years.
- Powder for preparation of suspension for intake: 3 years.
To use ready suspension within 14 days.
Not to use after the period of validity specified on packaging.

Storage conditions
- Capsules: at a temperature not above 30 °C in the place, unavailable to children.
- Solution for intravenous administration: at a temperature not above 30 °C in the place, unavailable to children. Not to allow freezing.
- Powder for preparation of suspension for intake: at a temperature not above 30 °C in the place, unavailable to children. To store ready suspension at a temperature not above 30 °C, not to freeze.

Issue conditions:

According to the recipe

Packaging:

- Capsules of 50 mg: on 7 capsules in the blister from PVC / aluminum foil; on 1 or 4 blisters together with the application instruction in a cardboard pack.
- Capsules of 100 mg: on 7 capsules in the blister from PVC / aluminum foil; on 1 or 4 blisters together with the application instruction in a cardboard pack.
- Capsules of 150 mg: on 1 or 4 capsules in the blister from PVC / aluminum foil;
on 1 blister together with the application instruction in a cardboard pack.
- Solution for intravenous administration of 2 mg/ml; on 25 ml, 50 ml, 100 ml or 200 ml of solution in the bottle from transparent besktsvetny glass like I corked by a rekzinovy stopper and which is pressed out by an aluminum cap with a plastic insert like "flip off". Flakkon is supplied by the plastic holder.
On 1 bottle together with the application instruction in a cardboard pack.
- Powder for preparation of suspension for intake of 50 mg / 5 ml or 200 mg / 5 ml in a plastic (PEVP) bottle with the screwing-up cover protecting from access for children and consisting of external (PEVP) and internal (software) of parts with the laying with a polymeric covering and also supplied with a plastic ring for control of the first opening. On 1 bottle together with a plastic measured spoon and the application instruction in a cardboard pack.