Difluzol solution

General characteristics. Structure:

Active ingredient: fluconazole; 100 ml of solution contain флуконазол 200 mg;

excipients: sodium chloride, water for injections.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a new class of triazolny antifungal means, powerful selection inhibitor of synthesis of sterol in cells of mushrooms.

Activity of a flukonazol at the opportunistic mycoses including caused by Candida spp is shown., including generalized candidiasis at animals with oppressed immunity; Cryptococcus neoformans, including intracranial infections; M_crosporum spp. itychophyton spp.

Also activity of a flukonazol on models of local mycoses at animals, in particular at the infections caused by Blastomyces dermatitides, Sossidioides _tt_tis (including intracranial infections) in_stoplasma is shown to capsulatum at animals with the normal and suppressed immunity.

Cases of the superinfection caused by types of Candida, others, than C. albicans which have natural nonsensitivity to a flukonazol are known (for example Candida krusei). Such cases demand alternative anti-mycotic therapy.

Flukonazol is high-specific to P450 cytochrome of dependent fungalny enzymes. Flukonazol in a dose of 50 mg a day within 28 days does not influence concentration of testosterone in plasma at men and concentration of steroid hormones at women of childbearing age.

Flukonazol in a daily dose from 200 to 400 mg does not render considerable clinical effect on the level of endogenous steroids or on the stimulated AKTG-answer at healthy male volunteers. Flukonazol in a dose of 50 mg at single or repeated use does not influence antipyrine metabolism.

Pharmacokinetics. Concentration of drug in a blood plasma is proportional to a dose. The equilibrium 90% concentration are reached for 4-5 days of treatment by drug at repeated use once a day.

Introduction of the first day of the shock dose twice exceeding a usual daily dose allows to reach equilibrium 90% of concentration for the second day. The actual volume of distribution of drug approaches the total amount of water in an organism.

Extent of linkng of a flukonazol with blood proteins does not exceed 11-12%.

Flukonazol reaches high penetration in all liquid environments of an organism. Drug levels in saliva and a phlegm are similar to its concentration in a blood plasma. At patients with fungal meningitis the level of a flukonazol in cerebrospinal fluid reaches 80% of its concentration in a blood plasma.

High concentration of a flukonazol in skin, above serumal indicators, are reached in a corneous layer, a layer epidermis derma and in sweat glands. Flukonazol collects in a corneous layer of skin. At use of drug in a dose of 50 mg once a day concentration of a flukonazol after 12 days makes 73 mkg/g, in 7 days after the treatment termination concentration makes 5,8 mkg/g. At use of 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, in 7 days after the second dose – 7,1 mkg/g.

Concentration of a flukonazol in nails after 4 months of reception of 150 mg once a week makes 4,05 mkg/g in healthy and 1,8 mkg/g – in sore nails; флуконазол is defined in tests of nails in 6 months after the end of treatment.

Drug is generally removed by kidneys, and about 80% of the entered dose are defined in urine in not changed look. The clearance of a flukonazol is proportional to clearance of creatinine. The circulating metabolites are absent.

Long plasma elimination half-life of blood which makes 30 h at oral administration in a dose of 150 mg once allows to enter флуконазол once at vaginal candidiasis and to apply once a day or once a week at other diseases.

Pharmacokinetic parameters of a flukonazol at children.

Pharmacokinetic parameters of a flukonazol at intravenous administration at children are specified in the table.

Age       of the child Doz                  of the drug Elimination Half-life Area under a curve
                                   (mg/kg)                           (hour)                            "concentration time"
                                                                                                               (AUC, mkg • hour/ml)

11 days-11 of month       Once 3 mg/kg                                                    23,0 110,1

 
5-15 years                  Repeatedly 2 mg/kg              17,4 *                                    67,4 *

5-15 years                   Repeatedly 4 mg/kg              15,2 *                                 139,1 *

5-15 years                   Repeatedly 8 mg/kg              17,6 *                                 196,7 *

 Notes: *-in the last day administrations of drug.

At prematurely born children (gestation term – about 28 weeks) after introduction of a flukonazol intravenously in a dose of 6 mg/kg every third day of at most 5 days an average elimination half-life sostavlyaet74 (44-185) hours in the 1st dens reduction till 53 (30-131) o'clock for the 7th day and till 47 (27-68) o'clock – on the 13th.

AUC (mkg • hour/ml) makes 271 (an interval 173-385) for the 1st day, increases up to an average value 490 (an interval 292-734) for the 7th day and decreases to an average value 360 (an interval 167-566) for the 13th day.

The volume of distribution (ml/kg) makes 1183 (interval of 1070-1470) for the 1st day, grows over time to an average value of 1184 (an interval 510-2130) for the 7th day and till 1328 (an interval of 1040-1680) for the 13th day.

Pharmacokinetic parameters of a flukonazol at people of advanced age.

Simultaneous use of diuretics considerably does not influence indicators of AUC or Cmax, besides, on clearance of creatinine (74 ml/min.). The percent of the recovered drug in not changed look in urine (0-24 h, 22%) and estimates of renal clearance of a flukonazol (0,124 ml/min.) for patients of advanced age is usually lower, than similar indicators at more young people. Therefore difference of accumulation of a flukonazol at patients of advanced age is connected with reduced indicators of function of kidneys at this group.

Patients of advanced age have high rates for pharmacokinetic parameters because of reduced function of kidneys that is natural at advanced age.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent colourless liquid.

Incompatibility.

Though cases of specific incompatibility of a flukonazol with other drugs are not described, it is not recommended to mix it with other drugs before infusion.

Indications to use:

Cryptococcosis, including cryptococcal meningitis and infections of other localization (for example lungs, skin). Treatment of carriers and patients with AIDS, patients after organ transplantation and other patients who receive therapy by immunosuppressants.

Flukonazol it is possible to apply какподдерживающуютерапиюс 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 (damage of an abdominal cavity, an endocardium, an eye, respiratory and urinary tract). Treatment of patients with malignant new growths which are in intensive care unit and receive cytostatic and immunosuppressive therapy or stay under the influence of other factors contributing to development of candidiases.

Candidiasis of mucous membranes: defeat of a stomatopharynx, a gullet, a noninvasive bronkhopulmonalnayainfektion, a kandiduriya, skin and mucous and chronic atrophic candidiasis (the candidiasis caused by a denture). Treatment of carriers and patients with AIDS. For prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS.

Genital candidiasis, including vaginal candidiasis, an acute or recurrent, and candidosis balanitis. Preventive use for the purpose of reduction of frequency of a recurrence of vaginal candidiasis (3 and more recurrence a year).

The prevention of a fungal infection at patients with malignant new growths which are predisposed to such infections owing to chemotherapy or radiation therapy.

Dermatomycoses – mycosis of feet, mycosis of gladenky skin, a pakhovy dermatomycosis, multi-colored deprive, deprive of nails (onychomycosis) and skin candidosis infections.

Deep local mycoses – at patients with the unimpaired immune system, кокцидиомикоз, паракокцидиомикоз, a sporotrichosis and histoplasmosis.

Route of administration and doses:

The daily dose of a flukonazol depends by nature and weights of a fungalny infection. Treatment of infections which demand multiple dose of drug to dolzhnoprodolzhatsya before achievement of clinical laboratory effect (attenuation of an active fungal infection). The insufficient duration of treatment can lead to resuming of active infectious process. The patients sick with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis, usually demand a maintenance therapy for the prevention of a recurrence. Therapy can be begun before obtaining results cultural or other laboratory researches, and at their receiving also germicides are added.

Adults.

At cryptococcal meningitis and cryptococcal infections of other localizations in the first day appoint 400 mg parenterally, and then continue treatment, applying doses from 200 to 400 mg of 1 times a day. Duration of treatment of a cryptococcal infection depends on the clinical and mycotic answer, but at least 6-8 weeks usually proceed at cryptococcal meningitis.

Treatment throughout very long term of Diflyuzolom® in a dose of 200 mg is shown for prevention of a recurrence of cryptococcal meningitis at patients with AIDS after end of a full course of primary treatment by them.

At a kandidemiya, the disseminated candidiasis and other forms of an invasive candidosis infection the dose, as a rule, makes 400 mg in the first days, and then – on 200 mg/days parenterally. Depending on degree of manifestation of clinical effect it is possible to increase a dose to 400 mg/days parenterally. Duration of therapy depends on clinical effect.

At oropharyngeal the kandidozeobychny dose makes from 50 to 100 mg of 1 times a day parenterally within 7-14 days. If necessary therapy can be considerable is prolonged at patients with heavy immunodisfunction.

At the atrophic candidiasis of an oral cavity connected with carrying dentures, the usual dose makes 50 mg of 1 times a day within 14 days, at the same time applying local antiseptic agents to processing of a prosthesis.

At other candidosis infections of a mucous membrane (a candidosis esophagitis, a noninvasive bronkhopulmonalny infection, a kandiduriya, skin and mucous candidiasis), except for genital candidiasis, the usual effective dose makes from 50 to 100 mg a day for 14-30 days.

For prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS after a full course of the main therapy флуконазол it is possible to appoint in a dose 150 mg once a week. It is possible to apply a dose of 150 mg to reduction of frequency of developing of repeated vaginal candidiasis once a month. Duration of treatment is defined individually, but has to make ranging from 4 up to 12 months. Some patients need more frequent use.

For prevention of candidiasis the recommended dose of a flukonazol makes 50-400 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 with the expected, expressed or long neutropenia) the recommended dose makes 400 mg of 1 times a day. Flukonazol appoint some days before the expected neutropenia; after the quantity of neutrophils exceeds 1000 in 1 mm3, treatment is continued within 7 days.

At skin infections (mycosis of feet, mycosis of gladenky skin, an inguinal dermatomycosis and candidosis infections) the recommended dose makes 150 mg parenterally once a week or 50 mg once a day. Usually treatment lasts 2-4 weeks, but at mycosis of feet can continue up to 6 weeks.

At multi-colored herpes the recommended dose makes 300 mg within 2 weeks once a week; to some patients treatment can be prolonged up to 3 weeks in the same dosage whereas for some patients can be enough and a single dose from 300 to 400 mg. The alternative mode of dosing – 50 mg parenterally 1 time a day within 2-4 weeks.

At mycosis of nails the recommended dose makes 150 mg once a week. Treatment should be continued before replacement of the affected nail (the healthy nail will grow so far). The period of recovery growth of nails on fingers of hands and legs normal lasts from 3 to 6 months and from 6 to 12 months respectively. This process can vary depending on specific features and age of the patient. After successful treatment of long persistent infection change of a shape of nails is sometimes observed.

At deep local mycoses need for a dose of drug from 200 to 400 mg a day during up to 2 years can appear. Duration of therapy is determined individually, but, as a rule, it makes 11-24 months for treatment of a koktsidiomikoz, 2-17 months – a parakoktsidiomikoz, 1-16 months – a sporotrichosis and 3-17 months – histoplasmosis.

Children.

Therapy duration at children, as well as at similar infections at adults, depends on clinical and anti-mycotic effect.

Children should not use drug in the daily dose exceeding that at adults. Flukonazol apply daily 1 time a day.

At candidiasis of mucous membranes the recommended dose makes 3 mg/kg/days. In the first day the shock dose – 6 mg/kg/days – for the purpose of more bystry achievement of constant equilibrium concentration 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 oppressed immunity at which the risk of development of an infection is connected with the neutropenia developing owing to cytotoxic chemotherapy or radiation therapy флуконазол appoint                      3-12 mg/kg/days depending on expressiveness and duration of the induced neutropenia.

Children aged up to 4 weeks.

At newborns флуконазол it is brought out of an organism more slowly. In the first 2 weeks of life флуконазол appoint in the same dose (at the rate on 1 kg of body weight), as to children of more advanced age, but bucketed for 72 hours. To children at the age of 3-4 weeks the same dose is entered with an interval on 48 hours.

Elderly people.

The patient of advanced age in the absence of symptoms of a renal failure drug is appointed in a usual dose.

For patients with an impaired renal function (the clearance of creatinine <50 ml/min.) the mode of dosing has to correspond given below.

Use to patients with a renal failure.

Flukonazol is brought generally with urine in not changed look. At single use it is not necessary to change a dose. Patients (including children) with a renal failure at repeated use of drug need to enter at first a shock dose which makes from 50 to 400 mg.

After introduction of a shock dose the daily dose (depending on indications) is determined by the table:

Clearance of creatinine, ml/min.                                 Percent of the recommended dose
 
>                                                                                    50 100%

≤ 50 (without dialysis)                                                                50%
 
 
The patients who are on regular dialysis        of 100% after each session of dialysis

Дифлюзол® enter intravenously by infusion with a speed no more than 10 ml/min.

Upon transition with intravenous to oral administration or on the contrary there is no need to change a daily dose.

Features of use:

In isolated cases use of a flukonazol can be followed by toxic damages of a liver, including with a lethal effect (generally they are observed at patients with serious associated diseases).

Emergence of the hepatotoxic effects connected with reception of a flukonazol does not depend on the general daily dose, duration of therapy, gender and age of the patient. A hepatotoxic action of a flukonazol, as a rule, reversible, its signs disappear after the therapy termination. It is necessary to watch patients at whom during treatment flukonazoly indicators of function of a liver, for the purpose of identification of signs of more severe damage of a liver are broken. At emergence of clinical signs of damage of a liver which can be connected with reception of a flukonazol drug needs to be cancelled.

During treatment flukonazoly exfoliative skin reactions, such as Stephens-Johnson's syndrome and a toxic epidermal necrolysis very seldom can occur at patients. Patients with AIDS are more inclined to heavy skin reactions because of use of a large number of drugs.

If the patient with a superficial fungal infection has a rash which can be connected with reception of a flukonazol, drug should be cancelled.

For patients with invasive/system fungal infections at emergence of rash it is necessary to observe and cancel fixedly флуконазол at emergence of violent defeats or a multiformny erythema.

It is necessary to watch the patients receiving at the same time флуконазол in a dose less than 400 mg a day with terfenadiny carefully.

Some azoles, including флуконазол, have communication with lengthening of an interval of QT on the electrocardiogram. Extremely isolated cases of lengthening of a QT interval and trembling of ventricles at seriously ill patients of the patients accepting флуконазол are possible (with numerous risk factors, organic heart diseases, disturbances of electrolytic exchange and need of therapy of associated diseases that they could be the factors promoting emergence of these disturbances). Flukonazol patients should appoint with care with these potentially pro-arhythmic states.

Features of use.

Therapy can be begun before obtaining results of laboratory researches, and at their receiving also germicides are added.

Compatibility

ДифлюзолÒдля intravenous administration it is compatible to the following solutions:
a) Ringer's solution;
b) Hartman's solution;
c) chloride potassium solution in Dextrosum;
d) 4,2% bicarbonate sodium solution;
e) аминофузин;

e) 0,9% chloride sodium solution.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Experience of use of a flukonazol demonstrates that deterioration in ability to drive the car and to work with other mechanisms, connected with administration of drug, is improbable.

Side effects:

Such undesirable reactions which emergence is connected using a flukonazol are possible:

central nervous sistema:golovny pain;

digestive тракт:боль in a stomach, diarrhea, a meteorism, nausea;

liver / желчевыделительная system: toxic damages of a liver, including isolated lethal cases, increase in level of an alkaline phosphatase, bilirubin, alaninaminotranspherase (ALT) and aspartate aminotransferase (ACT);

skin: rash.

At some patients, especially at seriously ill patients (AIDS or cancer), at treatment flukonazoly changes of indicators of blood, function of kidneys and a liver are possible, however clinical manifestations of these changes and their communication using solution of a flukonazol are not established.

The following undesirable phenomena are possible:

hemopoietic and lymphatic system: a leukopenia, including a neutropenia and an agranulocytosis, thrombocytopenia;

immune system: an anaphylaxis, including a Quincke's disease, a face edema and an itch of skin, a small tortoiseshell;

metabolic processes / features pitaniya:giperkholesterinemiya, gipertriglitseridemiya, hypopotassemia;

central and peripheral nervous system: dizziness, spasms, taste disturbances;

cordial system: lengthening of an interval of QT, Bouveret's ventricular disease like "pirouette";

digestive tract: digestion disturbance, vomiting;

liver / желчевыделительная system: liver failure, hepatitis, hepatocellular necrosis, jaundice;

skin and its derivatives: an allopecia, exfoliative skin reactions, including Stephens-Johnson's syndrome and a toxic epidermal necrolysis.

Interaction with other medicines:

Anticoagulants. The bleedings (formation of hematomas, bleeding from a nose, gastrointestinal bleedings, a hamaturia and a melena) connected with increase in a prothrombin time at the patients receiving флуконазол along with warfarin are possible. Careful control of a prothrombin time at patients who apply coumarinic anticoagulants is necessary.

Azithromycin. Simultaneous one-time oral administration of azithromycin in a dose of 1200 mg and a flukonazola in a dose of 800 mg inside does not lead to any significant pharmacokinetic interactions between flukonazoly and azithromycin. There is no significant influence on pharmacokinetics at interaction of a flukonazol and azithromycin.
Benzodiazepines (short action). At midazolam use inside use of a flukonazol leads to substantial increase of concentration of the first and to emergence of psychomotor reactions. This effect of midazolam is more expressed at reception of a flukonazol in capsules in comparison with flukonazoly, entered intravenously.

If the patient who receives treatment flukonazoly needs to appoint benzodiazepine, the dose of the last should be lowered, and for the patient to establish careful observation.
Tsizaprid. At simultaneous use of a flukonazol and tsizaprid isolated cases of undesirable reactions from heart are possible, including Bouveret's ventricular disease like "pirouette". Co-administration of a flukonazol     of 200 mg of 1 times a day and 20 mg of a tsizaprid 4 times a day leads to substantial increase of concentration of a tsizaprid in a blood plasma and to lengthening of an interval of QT. Purpose of a tsizaprid is contraindicated to patients who receive флуконазол.

Cyclosporine. At recipients of the replaced kidneys флуконазол in a dose of 200 mg/days slowly increases concentration of cyclosporine. However at multiple dose of a flukonazol on 100 mg/days of changes of level of cyclosporine at recipients of marrow it is noted. At treatment flukonazoly it is recommended to measure concentration of cyclosporine in blood.

Hydrochlorthiazidum. Repeated doses of Hydrochlorthiazidum lead to increase in concentration of a flukonazol in plasma for 40%. Influence on this indicator does not demand change in a dosage of a flukonazol from the patients applying diuretics, but doctors should not forget about possible interaction.

Oral contraceptives. Reception of 50 mg of a flukonazol significantly does not influence levels of hormones whereas at reception of 200 mg/days of a flukonazol increase in the area under a curve "concentration time" (AUC) of ethinylestradiol for 40% and a levonorgestrola for 24% is possible.

At reception of a flukonazol in a dose of 300 mg once a week AUC ethinylestradiol and norethindrone respectively 24% more and for 13%. It is improbable that multiple dose of a flukonazol in the given doses exerts a negative impact on efficiency of the combined oral contraceptives.

Phenytoinum. Simultaneous use of Diflyuzola®i of Phenytoinum can be followed by increase in concentration of Phenytoinum to clinically significant degree. If combined use of two drugs is necessary, monitoring of level of Phenytoinum and selection of its dose for ensuring therapeutic concentration in blood serum is required.

Rifabutin. Interaction of a flukonazol and rifabutin leads to increase in serumal levels of the last. At co-administration of a flukonazol and rifabutin uveitis cases are described. It is necessary to watch the patients receiving рифабутин and флуконазол at the same time carefully.

Rifampicin. Simultaneous use of a flukonazol and rifampicin leads to reduction of AUC by 25% and duration of an elimination half-life of a flukonazol for 20%. At the patients receiving at the same time rifampicin and флуконазол it is necessary to consider expediency of increase in a dose of the last.

Sulphonylurea drugs. Flukonazol at a concomitant use extends an elimination half-life of peroral drugs of sulphonylurea (Chlorproramidum, Glibenclamidum, a glipizid and Tolbutamidum).

Flukonazol and peroral drugs of sulphonylurea it is possible to appoint jointly a sick diabetes mellitus, but at the same time it is necessary to consider possible development of a hypoglycemia.

Takrolimus. Interaction of a flukonazol and takrolimus leads to increase in serumal levels of the last. At simultaneous use of a flukonazol and takrolimus chances of increase in nephrotoxicity. It is necessary to watch patients who receive такролимус and флуконазол at the same time carefully.

Terfenadin. At use of a flukonazol in a dose of 200 mg a day lengthening of an interval of QT is possible. Flukonazol in a dose of 400 mg a day and more considerably increases concentration of a terfenadin in a blood plasma. Simultaneous and more with terfenadiny it is contraindicated to the primenena of a flukonazol in doses of 400 mg a day. Treatment flukonazoly in doses less than 400 mg a day in combination with terfenadiny needs to be carried out under fixed control.

Theophylline. Reception of a flukonazol on 200 mg within 14 days leads to decrease in average speed of clearance of theophylline from plasma for 18%. At treatment flukonazoly the patients receiving theophylline in high doses, or patients with the increased risk of toxic effect of theophylline need to be watched theophylline overdose symptoms; at their emergence therapy should be changed properly.

Zidovudine. Simultaneous use with flukonazoly leads to increase in plasma concentration of a zidovudine. It is necessary to watch patients who accept such combination for the purpose of identification of side effects of a zidovudine.

Astemizol. Use of a flukonazol for the patients who are at the same time accepting астемизол or other drugs which are metabolized by system of P450 cytochrome can be followed by the increased concentration of these drugs in blood serum. In the absence of reliable information it is necessary to work carefully at co-administration of a flukonazol. It is necessary to watch patients fixedly.

The interaction research with other medicines was not conducted therefore interaction is potentially possible.

Contraindications:

Individual hypersensitivity to a flukonazol and to excipients or to other azolny substances close on chemical structure.

Simultaneous use of a terfenadin (at patients who accept ДифлюзолÒв to a dose of 400 mg a day and more).

Simultaneous use of a tsizaprid.

Overdose:

In isolated cases at overdose flukonazoly (8200 mg) developing of hallucinations and eksgibitsionichesky paranoid behavior is possible. In case of overdose there can be reasonable a symptomatic treatment (with the supporting actions and a gastric lavage if necessary).

Flukonazol is brought with urine therefore the artificial diuresis can accelerate drug removal. The session of a hemodialysis lasting 3 hours reduces the level of a flukonazol in plasma approximately by 50%.

Use during pregnancy or feeding by a breast. Adequate and well controlled researches at pregnant women were not conducted.

Chances of inborn defects at newborn children whose mothers within 3 months and more apply флуконазол in high doses (400-800 mg a day) to treatment of a koktsidiomikoz. Communication between these disturbances and reception of a flukonazol is not established.

It is necessary to avoid use of a flukonazol for pregnant women except for fungal infections which potentially threaten life (when the expected advantage of treatment exceeds potential risk for a fruit).

During feeding by a breast use of drug is not recommended.

Children. Children should not use drug in the daily dose exceeding that at adults.

Storage conditions:

Period of validity 1 year. To store in original packaging at a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 100 ml in a glass bottle, on 1 bottle in a pack.