Difluzol (capsules, 50 and 100 mg)

General characteristics. Structure:

Active ingredient: флуконазол;

1 capsule of a soderzhitflukonazol in terms of 100% substance of 50 mg or 100 mg;

vspomogatelnyeveshchestva:kaltion stearate, natriyakrakhmalglikolit (type A).

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a class of triazolny antifungal means, powerful selection inhibitor of synthesis of sterol in a cell of mushrooms. Drug is active at the mycoses caused by Candida spp., Cryptococcus neoformans, Microsporum spp., Trychoptyton spp., Blastomyces dermatitides, Coccidioides immitis, Histoplasma capsulatum.

Pharmacokinetics. After intake флуконазол it is well soaked up. The concomitant use of food does not influence absorption of drug at intake. Concentration in a blood plasma reaches the maximum value in 0,5-1,5 hours after administration of drug on an empty stomach. Contacts proteins of a blood plasma for 11-12%. The elimination half-life makes about 30 hours. Bioavailability after intake exceeds 90%.

Flukonazol well gets into all liquids of an organism. In a corneous layer, epidermis, a derma and stalemate liquid the concentration exceeding serumal are reached; флуконазол collects in a corneous layer.

It is removed generally by kidneys; about 80% of the accepted dose find in urine in an invariable look. The clearance of drug is proportional to clearance of creatinine.

Pharmaceutical characteristics.

Main physical and chemical properties: solid gelatin capsules No. 1, the case of turquoise color, a cover of pink color for a dosage of 50 mg, a cover of blue color for a dosage of 100 mg.

Contents of capsules – powder of white or almost white color, inodorous.

Indications to use:

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

Flukonazol it is possible to use as 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 (damage of an abdominal cavity, an endocardium, eyes, respiratory and urinary ways). Treatment of patients with malignant new growths which are in intensive care unit and receive cytostatic and immunosuppressive therapy, or are under the influence of other factors contributing to development of candidiasis.

Candidiasis of mucous membranes: defeats of a stomatopharynx, a gullet, a noninvasive bronkhopulmonalny infection, a kandiduriya, skin and mucous and chronic atrophic candidiasis (the candidiasis caused by a denture). Treatment of HIV 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 a himioterapiiila of 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, 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 not less than 6-8 weeks for cryptococcal meningitis usually last.

For the purpose of prevention of a recurrence of cryptococcal meningitis at patients with AIDS after end of a full course of primary treatment by them therapy flukonazoly in a dose of 200 mg/days can be continued throughout very long time.

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. Depending on degree of manifestation of clinical effect it is possible to increase a dose to 400 mg/days. Duration of therapy depends on clinical effect.

At oropharyngeal the kandidozeobychny dose makes from 50 to 100 mg of 1 times a day a current of 7-14 days. If necessary therapy can be continued during longer time to 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, etc.), 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 end of a full course of the main therapy флуконазол it is possible to appoint in a dose 150 mg once a week.

At vaginal candidiasis of Diflyuzol®prinimat in a dose of 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 from 4 to 12 months. Some patients need more frequent use.

флуконазол apply to treatment of a candidosis balanitis once in a dose 150 mg.

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 will exceed 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 once a week or 50 mg of 1 times a day. Usually  treatment  lasts 2-4 weeks, but at mycosis of feet can continue  to

6 weeks.

At multi-colored herpes the recommended dose makes 300 mg within          2 weeks once a week; at some patients treatment can be prolonged up to 3 weeks in the same dosage whereas for other 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 mycoses 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 not grow yet). The period of recovery  growth  of nails  on  fingers  of hands  and legs   normal lasts 3-6 months and

6-12 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 koktsidomikoz, 2-17 months – for a parakoktsidiomikoz, 1-16 months – for a sporotrichosis and 3-17 months – for histoplasmosis.

Children are more senior than 6 years.

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

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 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 больнымс 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.

Patients of advanced age.

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 in the table.

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 apply at first a shock dose which makes from 50 to 400 mg.

After use 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

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 lethal effects (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 at use of a large number of drugs. If the patient with a superficial fungal infection has a rash which can be connected with flukonazoly, 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 multimorfny 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.

In isolated cases, as well as for other azoles, anaphylactic reactions are possible.

Flukonazol influences lengthening of an interval of QT therefore patients should appoint it with care with possible development of arrhythmia: the inborn or acquired extended QT interval, a cardiomyopathy, especially at patients with heart failure, the sinus bradycardia, symptomatic arrhythmia, a concomitant use of the medicines extending QT interval are also not metabolized by CYP3A4 enzymes, a hypopotassemia, a hypomagnesiemia, a hypocalcemia.

Patients with potential tendency to arrhythmia флуконазол should appoint with care.

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

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 difficult mechanisms, connected with administration of drug, is improbable.

Side effects:

From a nervous system: headache, dizziness, вертиго, spasms, tremor, taste disturbance, sleeplessness, drowsiness, paresthesia.

From a digestive trakta:bol in a stomach, diarrhea, a meteorism, nausea, vomiting, dryness in a mouth, digestion disturbance.

From a storna to a gepatobiliarny sistemy:toksicheskia of damage of a liver, including isolated lethal cases, increase in level of enzymes of a liver (ALT, ACT, ShchF), bilirubin, a liver failure, hepatitis, hepatocellular damages, a cholestasia, jaundice.

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

From blood and lymphatic a sistemy:leykopeniya, including a neutropenia and an agranulocytosis, thrombocytopenia.

From immune a sistemy:anafilaksiya, including a Quincke's disease, a face edema and an itch of skin, a small tortoiseshell.

Metabolic narusheniya:giperkholesterinemiya, gipertriglitseridemiya, hypopotassemia.

From outside to a cardiovascular sistemy:udlinenia of an interval of QT, Bouveret's ventricular disease like "pirouette".

From skin and hypodermic a kletchatki:alopetion, the hung-up polivost, exfoliative dermatitis, including Stephens-Johnson's syndrome and a toxic epidermal necrolysis, rash, acute generalized exanthematous пустулез.

Drugoye:mialgiya, weakness, adynamy, fever.

Interaction with other medicines:

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

Azithromycin. Significant pharmacokinetic interactions between flukonazoly and azithromycin are noted.

Benzodiazepines (short action). Simultaneous use with midazolam leads to substantial increase of concentration of a flukonazol and to emergence of psychomotor reactions. This effect of midazolam is more expressed at reception of a flukonazol in capsules in comparison with flukonazoly which was entered intravenously. If the patient who receives treatment flukonazoly needs to appoint benzodiazepine, the dose of the last should be reduced, and for the patient to establish careful supervision.

Tsizaprid. At simultaneous use of a flukonazol and tsizaprid chances of undesirable reactions from heart, including Bouveret's ventricular disease like "pirouette". Co-administration of 200 mg of a flukonazol of 1 times a day and 20 mg of a tsizaprid 4 times a day leads to significant increase in concentration of a tsizaprid in a blood plasma and to lengthening of an interval of QT. To patients who receive флуконазол appointment is contraindicated to a tsizaprid.

Cyclosporine. At patients after transplantation of kidneys флуконазол in a dose of 200 mg/days slowly increases concentration of cyclosporine. However at repeated use of a flukonazol on 100 mg/days of change of level of cyclosporine at patients after transplantation of marrow were not noted. At treatment flukonazoly it is recommended to carry out monitoring of concentration of cyclosporine to blood.

Hydrochlorothiazide. Repeated doses of a hydrochlorothiazide lead to increase in plasma  concentration of a flukonazol. But it does not give the grounds for correction of the mode of dosing of a flukonazol to patients who in parallel accept diuretics. However it is necessary to remember 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 increase in the area under a curve concentration time (AUC) of ethinylestradiol for 40% and levonorgestrel for 24% was observed.

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 has a negative impact on efficiency of the combined oral contraceptives.

Phenytoinum. Simultaneous use of a flukonazol and Phenytoinum can be followed by essential increase in concentration of Phenytoinum to clinically significant degree.

If simultaneous use of two drugs is necessary, monitoring of level of Phenytoinum and selection of its dose for ensuring therapeutic concentration in blood serum is necessary.

Rifabutin. Simultaneous use of a flukonazol and rifabutin leads to increase in serumal level of a rifabutin, and also uveitis chances. Careful supervision for patients is necessary.

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 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 a possibility of development of a hypoglycemia.

Takrolimus. At interaction of a flukonazol and takrolimus there is an increase in serumal levels of the last. Cases of increase in nephrotoxicity at their simultaneous use are described.

Terfenadin (at doses of a flukonazol of 400 mg). Because of developing of serious cardiac arrhythmias in relation to lengthening of an interval of QT at the patients receiving azolny derivatives along with terfenadiny simultaneous treatment terfenadiny and doses of a flukonazol more than 400 mg are contraindicated.

Theophylline. Use of a flukonazol within 14 days leads to decrease in clearance of theophylline from a blood plasma. At emergence of symptoms of overdose by theophylline therapy should be changed properly.

Zidovudine. Simultaneous use with flukonazoly leads to increase in concentration of a zidovudine in a blood plasma. For patients careful supervision is necessary.

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

Erythromycin. Erythromycin increases concentration of a flukonazol in a blood plasma.

Pimozidum. Simultaneous use of a flukonazol with Pimozidum can lead to inhibition of metabolism of the last. Increase in concentration of Pimozidum in plasma can lead to lengthening of an interval of QT and exceptional cases of development of tachycardia like "pirouette". Simultaneous use of these drugs is contraindicated.

Amitriptyline. Flukonazol increases effect of amitriptyline. If necessary dosing of amitriptyline has to be corrected.

Amphotericinum. There are data on simultaneous use of a flukonazol and Amphotericinum at a preclinical stage that demonstrate weak additive effect at the infections caused by C. albicans, and antagonism of 2 drugs at the infections caused  by A. fumigatus. However these data are clinically not confirmed.

Carbamazepine. Flukonazol inhibits metabolism of carbamazepine and increases its content in blood serum by 30% therefore dose adjustment of the last is necessary.

Tselekoksib. At simultaneous use of a flukonazol (200 mg daily) and the tselekoksiba (200 mg) of Cmax and AUC of a tselekoksib increases by 68% and 134% respectively. In some cases there is a need for use of a half of a dose of a tselekoksib.

Cyclophosphamide. Simultaneous use of cyclophosphamide and a flukonazol leads to increase in bilirubin and creatinine in blood serum.

Fentanyl. Flukonazol considerably slows down fentanyl removal. The increased concentration of fentanyl can lead to respiratory depression and a lethal case.

GMK-KOA-reduktazy inhibitors. At simultaneous use of a flukonazol with GMK-KOA-reduktazy inhibitors which are metabolized by means of CYP3A4 (аторвастатин and симвастатин) and CYP2C9 (флувастатин), the risk of development of a myopathy and rabdomioliz increases. In case of need the accompanying therapy, the patient has to be inspected on existence of symptoms of a myopathy and a rabdomioliz, and also to control a kreatininkinaza. In case of existence of simtom of these diseases inhibitors of GMK-KOA-reduktazy should be cancelled.

Losartan. Flukonazol inhibits metabolism of a losartan in its active metabolite. Constant control behind the arterial pressure of the patients accepting at the same time флуконазол and лосартан is necessary.

Methadone. Flukonazol can increase concentration of methadone in blood serum. Methadone dosing correction is possible.

Non-steroidal anti-inflammatory drugs (NPVS). At simultaneous use of a flukonazol and flurbiprofen increase in Cmax and AUC of a flurbiprofen by 23% and 81% respectively is observed. Also at simultaneous use with a racemic ibuprofen (400 mg) Cmax and AUC increases by 15% and 82% respectively. Though, the potential of a flukonazol on systematic action of other NPVS is not up to the end studied, (for example, Naproxenum, to lomoksika, meloksika, diclofenac). Frequent control of possible side reactions and toxicity, connected with NPVS is necessary. Dose adjustment of NPVS is possible.

Prednisolonum. To patients who undergo prolonged treatment flukonazoly and Prednisonum, it is necessary to control possible development of insufficiency of bark of adrenal glands.

Because флуконазол is P450 inhibitor (an isoenzyme of CYP2C9 and CYP3A4), it is necessary to use the drugs which are metabolized by means of this enzymatic system with care. Alfentanil, blockers of calcium channels (nifedipine, исрадипин, амлодипин or фелодипин), галофантин, саквинавир, сиролимус, drugs of alkaloids of a periwinkle belong to such drugs (винкрастин, vinblastine). At simultaneous use of a flukonazol with these drugs monitoring of concentration of the last in blood and monitoring of possible development of the side reactions caused by these drugs is necessary.

Vitamin А.Данная the combination is possible, but side reactions from the central nervous system (benign intracranial hypertensia which passes after cancellation of a flukonazol) are possible.

There are data that for a flukonazol at joint reception with food, Cimetidinum, antacids and is applied along with total radiation of all organism after transplantation of marrow, absorbing properties practically do not change.

Interaction researches with other medicines were not conducted therefore interaction is potentially possible.

Contraindications:

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

Simultaneous use of the medicines extending an interval of QTI which are metabolized CYP3A4 enzymes (астемизол, Pimozidum, quinidine, терфенадин, цизаприд).

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 for 3 months and apply флуконазол in high doses more (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 to 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.

Use of drug in the form of capsules is possible to children from 6 years.

Overdose:

In isolated cases at overdose flukonazoly developing of hallucinations and paranoid behavior is possible. In case of overdose it is recommended immediate gastric lavages and a symptomatic treatment (including the supporting actions).

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 a blood plasma approximately by 50%.

Storage conditions:

Period of validity 4 years. To store in original packaging at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 50 mg No. 7 in the blister, capsules on 100 mg No. 7 in the blister.