Флунол®

General characteristics. Structure:

Active ingredient: 150 mg of a flukonazol.

Excipients: lactoses monohydrate of-146.150 mg, starch corn, silicon dioxide colloid anhydrous (Aerosil 200), sodium lauryl sulfate, magnesium stearate.

Structure of a cover of the capsule: capsule case: titanium dioxide (Е 171), gelatin,
capsule lid: ferrous oxide (III) red (Е 172), titanium dioxide (Е 171), gelatin.

Pharmacological properties:

Pharmacodynamics. ФЛУНОЛ® – the representative of triazolny antifungal means, is the selection inhibitor of synthesis of ergosterol in a membrane of fungi. Increases permeability of a cellular membrane, breaks its growth and replication. Pharmacological effect - fungicidal. Has specific effect on the fungal enzymes dependent on P450 cytochrome. Has no anti-androgenic activity.

Treatment flukonazoly in a dose of 50 mg/days within 28 days did not influence concentration of testosterone in blood at men or concentration of steroids at women of childbearing age. ФЛУНОЛ® it is effective at superficial and system fungal infections which are caused by Candida spp., Cryptococcus neoformans, Coccidiodes immitis, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Histoplasma capsulatum.

Pharmacokinetics. Flukonazol is well soaked up after oral administration, bioavailability makes more than 90%. Meal does not influence absorbability of drug. The maximum concentration is reached in 0,5 – 1,5 hours. Flukonazol well gets into fluid mediums of an organism. Levels of a flukonazol in saliva, a phlegm approach its concentration in plasma. At patients with fungal meningitis the level of a flukonazol in cerebrospinal fluid makes about 80% of level it in plasma.

In a corneous layer of epidermis, a derma and sweat glands high concentration of a flukonazol which exceed serumal are reached. Flukonazol badly contacts proteins of plasma (12%). The elimination half-life makes 30 hours. Is not exposed to metabolism. Metabolites of a flukonazol in peripheral blood are not revealed. Flukonazol is brought preferential by kidneys, about 80% of the accepted dose are found in urine in not changed look.

Indications to use:

- orofaringealny candidiasis;
- acute or recurrent vaginal candidiasis;
- candidosis balanitis;
- system candidiasis, including a kandidemiya, the disseminated candidiasis and other forms of an invasive candidosis infection (an infection of a peritoneum, an endocardium, eyes, respiratory and urinary tract);
- the cryptococcosis including cryptococcal meningitis and fungal infections of others of localization (lungs, skin);
- skin mycoses: mycoses of feet, smooth skin of a trunk, a chromophytosis, the skin infections caused by a type of Candida, an onychomycosis;
- prevention of fungal infections at patients with malignant tumors against the background of himio-or radiation therapy.

Route of administration and doses:

Adult:
- at oropharyngeal candidiasis in the first day drug is usually appointed on 200 mg, then continue 100 mg once a day (use of the capsules "ФЛУНОЛ® 100", 100 of mg is recommended). Treatment is continued within 2 weeks to reduce probability of a recurrence.
- at vaginal candidiasis accept once inside in a dose 150 mg. For decrease in frequency of a recurrence of vaginal candidiasis drug can be used in a dose of 150 mg once a month. Duration of therapy is determined individually – it varies from 4 to 12 months.
- at chronic recurrent vulvovaginal candidiasis (frequency of a recurrence of 4 and more times a year) it is recommended pulse therapy: on 150 mg once a week within 1-3 months.
- at a candidosis balanitis – once 150 mg.
- at system candidiasis, a kandidemiya and other forms of an invasive candidosis infection accept in a dose 400 mg in the first days, and then on 200 mg once a day (use of the capsules "ФЛУНОЛ® 100", 100 of mg is recommended). Duration of therapy depends on clinical and mycologic performance.
- at cryptococcal meningitis and cryptococcal infections in the first day accept 400 mg in a dose, and then continue treatment in a dose of 200 mg of 1 times a day (use of the capsules "ФЛУНОЛ® 100", 100 of mg is recommended). 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.
- at skin mycosis the recommended dose makes 150 mg once a week. Therapy duration in everyday occurences makes 2-4 weeks, however at mycoses of feet longer therapy can be required (up to 6 weeks).
- at an onychomycosis the recommended dose of 150 mg once a week. Treatment should be continued before growth of not infected nail. Repeated growth of nails on fingers of hands and feet normal requires 3-6 and 6-12 months respectively.
- at a chromophytosis of 300 mg once a week, within 2 weeks.
- for prevention of fungal infections at patients with malignant tumors the recommended dose 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 one in time days.

Use for children. As well as at adults, at similar infections, duration of treatment depends on clinical and mycologic effect.

The maximum daily dose for adults should not be exceeded at children. Flukonazol is accepted every day in a single dose. At candidiasis of mucous membranes the dose 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 an immunodeficiency considered in risk group owing to a neutropenia, receiving 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.

Use for elderly people. In the absence of symptoms of a renal failure drug is appointed in a usual dose.

Use for patients with a renal failure. 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.)     the Interval between doses/percent of the recommended dose
>                                                   50 100%
≤50 (without dialysis)                                50%
Regular dialysis                              of 100% after each dialysis

Patients on regular dialysis have to receive 100% of the recommended dose after each dialysis; in days, when there is no dialysis, patients have to receive the reduced dose according to their clearance of creatinine.

Features of use:

Treatment needs to be continued before emergence of kliniko-mycologic remission of a disease. The premature termination of treatment leads to a recurrence. Treatment can be begun before obtaining results of crops or other laboratory analyses, with the subsequent correction of fungicidal therapy by the received results of researches. During treatment it is necessary to control blood indicators, function of kidneys and a liver.

At emergence of renal failures and a liver it is necessary to stop administration of drug. In rare instances use of a flukonazol was followed by toxic changes of a liver, including with a lethal outcome, mainly, at patients with associated diseases. Patients at whom during treatment flukonazoly indicators of function of a liver are broken need to be observed for the purpose of identification of signs of 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. The hepatotoxic action of a flukonazol is usually reversible, symptoms disappear after the therapy termination.

When developing skin rashes at patients with an immunosuppression careful observation is necessary, and in case of progressing of skin reaction it is necessary to stop treatment (danger of development of a syndrome of Stephens-Johnson, a Lyell's disease).

Patients with AIDS are more inclined to development of heavy skin reactions. At emergence in the patient receiving drug concerning a superficial fungal infection, rash which can be connected with flukonazoly it is necessary to cancel. At emergence of rash in patients with their invasive/system fungal infections it is necessary to observe and cancel carefully флуконазол at emergence of violent defeats or a multiformny erythema. Anaphylactic reactions were in rare instances observed.

Flukonazol can cause increase in an interval of QT at an ECG. At use of a flukonazol increase in an interval of QT and blinking/trembling of ventricles noted very seldom at patients 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 ФЛУНОЛ® with care.

Patients with diseases of a liver, heart and kidneys before use ФЛУНОЛ® are recommended to consult with the doctor.

At use of Флунола® 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 it is necessary to see a doctor.

Flukonazol is CYP2C9 inhibitor of strong action by CYP3A4 inhibitor of average action. The patients accepting treatment flukonazoly who accept the accompanying therapy by drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 have to be inspected.

Ö½Ò¡«½® 150 it has to be taken with caution by patients with renal dysfunction.

Pediatric population. Examples and cases of the undesirable phenomena, and laboratory aberrations which were observed at children are comparable with those phenomena which were observed at adults.

Features of influence of medicine on ability to manage the vehicle or potentially dangerous mechanisms. Patients should be informed on the danger connected with control of automobiles, service of the mechanical equipment and other potentially dangerous types of activity.

Side effects:

Often (from ≥1/100 to <1/10):
- headache;
- abdominal pain, diarrhea, nausea, vomiting;
- increase in level of an alkaline phosphatase, serumal level of aminotransferases (ALT and nuclear heating plant);
- rash;
Infrequently (from ≥1/1,000 to ≤1/100):
- sleeplessness, drowsiness;
- spasms, dizziness, paresthesia, taste change;
- вертиго;
- dyspepsia, a meteorism, dryness in a mouth;
- a cholestasia, jaundice, the raised bilirubin;
- an itch, urticaria, the increased sweating, dermatitis;
- mialgiya;
- fatigue, indisposition, weakness, fervescence.
Seldom (from ≥1/10,000 to ≤1/1,000):
- agranulocytosis, leukopenia, neutropenia, thrombocytopenia;
- anaphylaxis, Quincke's disease;
- gipertriglitseridemiya, hypercholesterolemia, hypopotassemia;
- tremor;
- tachycardia, blinking/trembling of ventricles, increase in an interval of QT;
- a hepatotoxic, including exceptional cases with a lethal outcome, a liver failure, a hepatocellular necrosis, hepatitis, hepatocellular damages;
- toxic epidermal necrolysis, Stephens-Johnson's syndrome, acute generalized exanthematous пустулез, exfoliative dermatitis, face edema, alopecia.

At patients with AIDS or cancer, at treatment flukonazoly and similar drugs changes of indicators of blood, function of kidneys and a liver were observed, however clinical value of these changes and their communication with treatment are not established.

Interaction with other medicines:

At simultaneous use of a flukonazol:
- with coumarinic anticoagulants - флуконазол increases a prothrombin time. The patients receiving coumarinic anticoagulants have to be under strict medical control;
- with tsizapridy - cases of the undesirable phenomena from heart are described, including paroxysms of ventricular tachycardia (arrhythmia like "pirouette");
- with cyclosporine - control of concentration of cyclosporine in blood as its increase is possible is recommended;
- with a hydrochlorothiazide - leads to increase in concentration of a flukonazol in blood for 40%. However it does not demand change of the mode of dosing;
- with ethinylestradiol and levonorgestrel - флуконазол "concentration time" (AUC) increases their areas under a curve. However it does not exert impact on efficiency of the combined peroral contraceptive drug;
- with Phenytoinum - increase in concentration of Phenytoinum substantially can be observed. In need of use of the combined treatment with Phenytoinum, control of level of the last, and adequate selection of a dose is necessary for ensuring therapeutic concentration in serum;
- with rifampicin - leads to decrease in AUC of a flukonazol by 25% and T1/2 by 20%. At the patients receiving combined rifampicin it is necessary to consider expediency of increase in a dose of a flukonazol;
- with peroral hypoglycemic means (sulphonylurea derivatives) - флуконазол extends their elimination half-life. Frequent control of glucose of blood and the corresponding reduction of a dose of sulphonylurea is recommended;
- with antifungal drugs from group of azolny derivatives, with terfenadiny and astemizoly - the probability of development of serious arrhythmias with lengthening of an interval of QT (in need of use of such combination careful medical control is required) increases;
- with theophylline - lengthening of an elimination half-life of theophylline from plasma and development of symptoms of its overdose is possible;
- with a zidovudine - leads to increase in concentration of a zidovudine in plasma. The patients receiving such combination should be observed for the purpose of identification of side effects of a zidovudine;
- with antipyrine - флуконазол in a dose of 50 mg does not influence antipyrine metabolism;
- with midazolam – флуконазол significantly increases concentration of midazolam and psychomotor effects;
- with triazolamy - raises AUC of a triazolam (a single dose) approximately for 50%, Cmax for 20-32% and t½ for 25-50%, because of inhibition of metabolism of a triazolam. Dose adjustment of a triazolam can be required;
- with benzodiazepines - careful observation for the purpose of the corresponding dose decline of benzodiazepine is necessary;
- with blockers of slow calcium channels (nifedipine, isradipiny, amlodipiny, verapamil and felodipiny) - флуконазол  can increase considerably system influence of antagonists of calcium channels. Frequent monitoring on side effect of drugs is recommended;
- with non-steroidal anti-inflammatory drugs (tselekoksiby, flurbiprofeny, an ibuprofen, Naproxenum, lornoksikamy, meloksikamy, diclofenac) – increases Cmax and AUC NPVP. Frequent monitoring on the side effect and toxicity connected with NPVP is recommended. Dose adjustment of NPVP can be required;
- with cyclophosphamide - increases levels of bilirubin and creatinine in blood serum. The combination can be used before the risk of increase in levels of bilirubin and creatinine in blood serum appears;
- with fentanyl - флуконазол considerably detains fentanyl elimination. The increased concentration of fentanyl can result in respiratory insufficiency;
- alfentanil: at simultaneous therapy with flukonazoly decrease in clearance and volume of distribution, and also lengthening of the period of removal of alfentanil is observed. The possible mechanism of action is the inhibition flukonazoly CYP3A4 enzyme. Alfentanil dose adjustment can be required. 
- with galofantriny – флуконазол can increase concentration of a galofantrin in plasma because of the inhibiting effect on CYP3A4;
- with inhibitors of hydroxymethylglutaryl-A-reductase (GMG-KOA-reduktazy) - the risk of development of a myopathy and acute necrosis of skeletal muscles increases (рабдомиолиз) when флуконазол appoint along with GMG-KOA-reduktazy inhibitors which are metabolized through CYP3A4, such as аторвастатин and симвастатин, or through CYP2C9, such as флувастатин. If the accompanying therapy is necessary, the patient has to be observed on emergence of symptoms of a myopathy and rabdomioliz, and also control of level of a creatine kinase has to be carried out. Reception of GMG-KOA-reduktazy inhibitors should be stopped if substantial increase of level of a creatine kinase is observed or if it is diagnosed or development of a myopathy / рабдомиолиза is suspected;
- with losartany - флуконазол inhibits metabolism of a losartan to its active metabolite (E-31 74) which is responsible for the most part of antagonism of receptors of angiotensin II which occurs during treatment losartany. Patients have to control arterial pressure constantly;
- with methadone – concentration of methadone in blood serum increases, methadone dose adjustment can be required;
- with periwinkle alkaloid - can increase plasma levels of alkaloid of a periwinkle (for example, Vincristinum and vinblastine) and to lead to a neurotoxicity, because of an inhibiting effect on CYP3A4;
- with vitamin A – careful observation of patients for the purpose of identification of the side effects connected with TsNS is required;
- with vorikonazoly - co-administration of a vorikonazol and flukonazol in any dose is not recommended. Simultaneous use of a peroral vorikonazol (to 400 mg there are each 12 hours in 1 day, then to 200 mg there are each 12 hours within 2,5 days) and a peroral flukonazol (400 mg in the 1st day, then to 200 mg there are each 24 hours within 4 days) led to increase in concentration and AUC of a vorikonazol on average by 57% (9% of CI: 20%, 107%) and 79% (90% of CI: 40%, 128%), respectively;
- with Cimetidinum, antacids - do not observe clinically significant influence on absorption of a flukonazol;
- with Prednisolonum - the patients who are on prolonged treatment flukonazoly and Prednisolonum have to be under control on development of insufficiency of bark of adrenal glands after cancellation of reception of a flukonazol;
- with rifabutiny – increases levels of a rifabutin in blood serum to 80%. It was reported about cases of development of a uveitis in patients which at the same time appointed флуконазол and рифабутин. Careful control of a condition of the patients receiving рифабутин and флуконазол at the same time is necessary;
- with sakvinaviry - AUC of a sakvinavir approximately increases by 50%, Cmax approximately for 55% and reduces clearance of a sakvinavir approximately by 50% at the expense of inhibition of hepatic metabolism of a sakvinavir by means of CYP3A4 and inhibition of the R-glycoprotein. Dose adjustment of a sakvinavir can be required;
- with sirolimusy - plasma concentration of a sirolimus, presumably, by inhibition of metabolism of a sirolimus by means of CYP3A4 and the R-glycoprotein increases. This combination can be used at dose adjustment of a sirolimus depending on measurements of effect / concentration;
- with takrolimusy -  serumal concentration of a takrolimus at oral administration to 5 times at the expense of inhibition of metabolism of a takrolimus in intestines by means of CYP3A4 can increase. No essential pharmacokinetic changes at intravenous administration of a takrolimus were revealed. Increase in level of a takrolimus was connected with nephrotoxicity. The dosage of a peroral takrolimus has to be lowered depending on concentration of drug;
- amitriptyline, нортриптилин: флуконазол strengthens effect of amitriptyline and a nortriptilin. Concentration of a 5-nortriptilin and/or S-amitriptyline can be measured in the beginning of a combination therapy and in a week. If it is necessary, amitriptyline doses / нортриптилина have to be corrected;
- carbamazepine: флуконазол inhibits metabolism of carbamazepine and increases concentration of the last in blood serum for 30%. There is a risk карбамазепиново   й toxicity. Dose adjustment of carbamazepine depending on measurements of concentration/effect can be required.

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 multiple dose of a flukonazol in a dose of 400 mg/days and more;
- a concomitant use of the medicines extending an interval of QT and which are metabolized by means of CYP3A4 enzyme such, as цизаприд, астемизол, erythromycin, Pimozidum and quinidine;
- hereditary lactose intolerance, deficit of Lapp-lactases enzyme, glucose galactose malabsorption;
- pregnancy and period of a lactation;
- children's age up to 12 years.

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: the supporting and symptomatic therapy, if necessary, a gastric lavage is applied. As флуконазол it is excreted preferential with urine, the artificial diuresis possibly has to increase elimination speed. The session of a 3-hour hemodialysis reduces concentration of a flukonazol in plasma approximately by 50%.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children! Period of storage 4 years. Not to apply after the storage expiration.

Issue conditions:

According to the recipe

Packaging:

On the 1 or 2 capsule in a blister strip packaging from a film of polyvinyl chloride and printing aluminum foil.

On 1 blister strip packaging together with the instruction on a medical use in the state and Russian languages place in a pack cardboard with the hologram of manufacturing firm.