Capsule difluzol

General characteristics. Structure:

Active ingredient: флуконазол;

1 capsule of a soderzhitflukonazol, in terms of 100% substance of 150 mg;

vspomogatelnyeveshchestva:kaltion stearate, natriyakrakhmalglikolit (type A).

Dosage form. Capsules.

Solid gelatin capsules No. 1, case of turquoise color, cover of green color. Contents of capsules – powder of white or almost white color, inodorous.

Pharmacological properties:

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

The beginning of stopping of symptoms after use of 150 mg of a flukonazol in the form of a single dose from 1 hour to 9 days – on average 1 days.

Chances of the superinfection caused by types of Candida, others except S. albicans which have natural nonsensitivity to a flukonazol (for example, Candidakrusei). Such cases demand alternative anti-mycotic therapy.

Flukonazol is high-specific to tsitokhroma of P450 of dependent fungalny enzymes.

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.

Indications to use:

Vaginal candidiases at patients who were previously diagnosed (or are shown incidentally) by the doctor.

Route of administration and doses:

Adults.

For treatment of vaginal candidiasis of Diflyuzol® accept once in a dose 150 mg.

Patients of advanced age.

Treatment using a single dose of 150 mg of a flukonazol to patients is aged more senior than 60 years without supervision of the doctor it is not recommended.

Use by the patient with a renal failure.

Flukonazol is brought generally with urine in an invariable look. At a single dose of a flukonazol the patient with the initial and moderated degrees of a renal failure to change a dose there is no need.

Clearance of creatinine, ml/min.                                  Percent of the recommended dose
           
>                                                                                    50 100%
≤ 50                                                                                     50%
 
The patients who are on regular dialysis         of 100% after each session of dialysis

Features of use:

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 and women of reproductive age without use of adequate contraception.

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

Children.

Have not enough information on use of a flukonazol in a single dose of 150 mg for treatment of vaginal candidiasis children.

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, dyspepsia, nausea, vomiting, dryness in a mouth, digestion disturbance.

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, a skin itch, a small tortoiseshell.

Metabolic narusheniya:giperkholesterinemiya, gipertriglitseridemiya, hypopotassemia.

From cardiovascular system: lengthening of an interval of QT, Bouveret's ventricular disease like "pirouette".

From a storna of gepatobiliarny system: toxic damages 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.

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:

The interactions given below arise at repeated use of drug and are noted at single use.

Patients who at the same time apply other medicines should consult with the doctor before an initiation of treatment flukonazoly.

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 lengthenings of an interval of QT. Purpose of a tsizaprid is contraindicated to patients who receive флуконазол.

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 a rezhimadozirovaniye to patients who in parallel prinimayutdiuretik. 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 observe increase in the area under a curve concentration time (AUC) of ethinylestradiol for 40% and levonorgestrel for 24%. 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 combined use of two drugs is necessary, monitoring of level of Phenytoinum and selection of its dose is necessary for ensuring therapeutic concentration in blood serum.

Rifabutin. Simultaneous use of a flukonazol with rifabutiny leads to increase in level of a rifabutin in blood serum, 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. Careful observation is necessary.

Terfenadin (at doses of a flukonazol of 400 mg). Because of development of serious cardiac arrhythmias, in relation to lengthening of a QT interval 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 to patients, 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 use 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:

Individual hypersensitivity to a flukonazol and to excipients or to other azolny substances close to it on chemical structure. Simultaneous use of the medicines extending an interval of QTI which are metabolized CYP3A4 enzymes (астемизол, Pimozidum, quinidine, терфенадин, цизаприд).

Appropriate security measures at 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).

In case of the hepatotoxic effects connected with reception of a flukonazol their explicit dependence on the general daily dose, duration of therapy, gender and age of the patient is noted. 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 flukonazoly 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 krazvitiyutyazhelykhkozhnykhreaktsiypr of primeneniibolshy amount of drugs. If the patient with a superficial fungal infection has a rash which can be connected with flukonazoly, drug should be cancelled.

In isolated cases, as well as for other azoles, a vozmozhnovozniknoveniye of anaphylactic reactions.

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.

Flukonazol patients should appoint with care with potential tendency to arrhythmia.

Patients with diseases of a liver, heart and kidneys need to consult with the doctor before an initiation of treatment flukonazoly.

Positive dynamics of symptoms usually begins in 24 hours. However their total disappearance can happen for several days. If for several days the patient had no improvement, it is necessary to see a doctor.

Overdose:

In isolated cases at overdose flukonazoly developing of hallucinations and paranoid behavior is possible. In case of overdose the immediate gastric lavage and a symptomatic treatment is recommended (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 150 mg No. 1 in the blister, 1 or 2 blisters in a pack, or No. 2 in the blister, 1 blister in a pack.