Flukonazol - Teva

General characteristics. Structure:

Contains in 1 capsule:
active agent флуконазол 50,00 mg, 100,00 mg or 150,00 mg;
excipients: lactoses monohydrate, starch corn, silicon dioxide colloid, sodium lauryl sulfate, magnesium stearate.
Gelatin capsule:
Case: titanium dioxide (E171), diamond blue FCF (E133) (contains only in a dosage of 150 mg), gelatin.
Cover: titanium dioxide (E171), diamond blue FCF (E133), gelatin.

Description
Dosage of 50 mg: solid gelatin capsules No. 4 with opaque a cover of light blue color and the case of white color.
Dosage of 100 mg: solid gelatin capsules No. 2 with opaque a cover of dark-blue color and the case of white color.
Dosage of 150 mg: solid gelatin capsules No. 1 with an opaque cover and the case of light blue color.
Contents of capsules: homogeneous powder of color, white or white with a yellowish shade.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a class of triazolny antifungal means, cytochrome of P450-dependent enzymes, including 14 - alpha деметилазы, catalyzing reaction of transformation of a lanosterol into ergosterol that leads to ergosterol synthesis blocking, disturbance of structure and function of a cellular membrane of mushrooms is highly specific inhibitor of activity.

Flukonazol shows high antifungal activity concerning Candida albicans and other Candida spp., Cryptococcus spp. 40% of Candida glabrata have primary resistance to a flukonazol, Candida krusei, Aspergillus spp. and Mucor spp. are steady against a flukonazol.

Pharmacokinetics. The pharmacokinetics of a flukonazol at intake is similar to pharmacokinetics at intravenous (in) introduction.

Absorption
After intake флуконазол it is well absorbed, its concentration in plasma (and the general bioavailability) exceeds 90% of concentration of a flukonazol in plasma later in/in introductions. The concomitant use of food does not influence absorption at intake. The maximum concentration (Cmax) is reached in 0,5-1,5 h after reception of a flukonazol on an empty stomach. Concentration in plasma is proportional to a dose. At reception of the recommended daily dose once a day equilibrium concentration (Css) reaches 90% by 4-5th day of treatment by drug. Introduction in the 1st day of the shock dose twice exceeding an average daily dose allows to accelerate achievement of Css of equal 90% by 2nd day.

Distribution
The seeming volume of distribution approaches the general content of water in an organism. Linkng with proteins low (11-12%).
Flukonazol well gets into many liquids of an organism. Concentration of a flukonazol in saliva, a phlegm, breast milk, joint liquid and peritoneal liquid is similar to its concentration in plasma. Constant values in a vaginal secret are reached in 8 h after intake and keep at this level not less than 24 h. At patients with fungal meningitis concentration of a flukonazol in cerebrospinal fluid makes about 80% of its concentration in plasma. In a corneous layer of epidermis, epidermis derma and stalemate liquid high concentration which exceed serumal are reached. Flukonazol collects in a corneous layer of epidermis. At reception in a dose of 50 mg of 1 times/days concentration of a flukonazol in 12 days made 73 mkg/g, and in 7 days after the treatment termination - only 5,8 mkg/g. At use in a dose of 150 mg of 1 time/week concentration of a flukonazol in a corneous layer for the 7th day made 23,4 mkg/g, and in 7 days after reception of the second dose - 7,1 mkg/g. Concentration of a flukonazol in nail plates after 4-month use in a dose of 150 mg of 1 time/week made 4,05 mkg/g in healthy and 1,8 mkg/g in the affected nails; in 6 months after completion of therapy флуконазол was, still, defined in nail plates.

Metabolism and removal
Flukonazol is brought generally by kidneys; about 80% of the entered dose find in urine in not changed look. The clearance of a flukonazol is proportional to clearance of creatinine. The circulating metabolites are not found. The long elimination half-life (T1/2) from plasma allows to accept флуконазол once at vaginal candidiasis and 1 times/days or 1 time/week at other indications.

Indications to use:

• Genital candidiasis. Acute or recurrent vaginal candidiasis, at inefficiency of topical treatment.
• Candidiasis of mucous membranes, including mucous membranes of an oral cavity and a throat, a gullet, noninvasive bronchopulmonary candidiasis, a kandiduriya, the skin and mucous and chronic atrophic candidiasis of an oral cavity (connected with carrying dentures at inefficiency of topical treatment).
• Skin mycoses, including mycoses of feet, bodies, inguinal area, a chromophytosis, onychomycoses and skin candidosis infections.
• Generalized candidiasis, including a kandidemiya, the disseminated candidiasis and other invasive candidosis infections with damage of abdominal organs, an endocardium, eyes, a respiratory organs and urinogenital bodies, including at the patients receiving cytotoxic or immunodepressive means.
• Cryptococcal meningitis at patients with a normal immune response, patients with the unspecified reason of an immunosuppression, patients with AIDS, recipients of transplanted organs and patients with the immunodeficiency caused by other reasons; a maintenance therapy for the purpose of prevention of a recurrence of a cryptococcosis at patients with AIDS.
• Prevention of fungal infections at patients with malignant tumors against the background of cytotoxic chemotherapy or radiation therapy.

Route of administration and doses:

Inside irrespective of meal.
Capsules should be swallowed entirely, washing down with a glass of water.
The daily dose of a flukonazol depends on character and weight of a fungal infection.

Adults
Vaginal candidiasis: once 150 mg.
Candidiasis of mucous membranes of an oral cavity and throat: 50 mg of 1 times/days within 7-14 days. Normal treatment should not exceed 14 days, except for patients with heavy disturbance of immunity.
The chronic atrophic candidiasis of an oral cavity connected with carrying dentures: 50 mg once a day within 14 days in combination with local antiseptic agents.
Other candidosis infections of mucous membranes (except for the vaginal candidiasis described above), for example, at an esophagitis, noninvasive bronchopulmonary infections, mucous and skin candidiasis, etc.: 50 mg a day within 14-30 days.
In hard cases of candidosis infections of mucous membranes, in particular at a recurrence, the daily dose can be increased to 100 mg/days.
Skin mycoses, including mycoses of feet, bodies, inguinal area and skin candidosis infections: 150 mg of 1 time/week or 50 mg of 1 times/days. Therapy duration in everyday occurences makes 2-4 weeks, however at mycoses of feet longer therapy can be required (up to 6 weeks).
Onychomycosis: 150 mg of 1 time/week. Treatment should be continued before substitution of the infected nail (growth of not infected nail). Repeated growth of nails on fingers of hands and legs usually requires 3-6 and 6-12 months, respectively. However growth rate can vary over a wide range at different people, and also depending on age. After successful treatment it is long the remaining persistent infections sometimes change of a shape of nails is observed.

Chromophytosis: 300 mg of 1 time/week within 2 weeks; some patients need the third dose of 300 mg/week while for some patients the single dose of drug in a dose of 300-400 mg is accorded sufficient. The alternative scheme of treatment - on 50 mg of 1 times/days within 2-4 weeks.
Kandidemiya, the disseminated candidiasis and other invasive candidosis infections: on average 400 mg in the first days, and then on 200 mg/days. Depending on expressiveness of clinical effect the dose can be increased to 400 mg/days. Duration of therapy depends on clinical performance.
Cryptococcal meningitis: in the first day on average 400 mg, then 200-400 mg of 1 times/days. Duration of treatment of cryptococcal infections depends on existence of clinical and mycologic effect, treatment is usually continued by not less than 6-8 weeks. Prevention of a recurrence of cryptococcal meningitis at patients with AIDS: after end of a full course of primary treatment therapy flukonazoly in a dose of 200 mg/days can be continued during very long term.
Prevention of candidiasis: 50-400 mg of 1 times/days depending on a risk degree of development of a fungal infection. With high risk of a generalized infection, for example, at patients from expressed or it is long the remaining neutropenia after carrying out cytotoxic chemotherapy or radiation therapy, the recommended dose makes 400 mg of 1 time/days Flukonazol appoint some days before the expected emergence of a neutropenia and after increase in number of neutrophils more 1000/mkl treatment is continued within 7 days.

Children are more senior than 16 years
The route of administration and doses - as well as at similar infections at adults, duration of treatment depends on clinical and mycologic effect. The maximum daily dose for children of 400 mg. Flukonazol apply daily 1 times/days.

Use for children with a renal failure: see below "Patients with a renal failure".

Elderly patents
In the absence of symptoms of a renal failure drug is used in a standard dose.

Patients with a renal failure
Flukonazol is brought generally with urine in not changed look. At a single dose change of a dose is not required. At patients, including children, with renal failures at repeated use of drug it is necessary to enter originally a "shock" dose from 50 mg to 400 mg then the daily dose is determined depending on indications by the following table.

Clearance of creatinine (ml/min.)                               Percent from the recommended dose
>                                                                          50 100%
<50 (without dialysis)                                                    50%
The patients residing on dialysis    of 100% after each session of dialysis

Features of use:

Treatment needs to be continued before emergence of kliniko-mycologic remission. The premature termination of treatment leads to a recurrence. Treatment can be begun in the absence of results of crops and other laboratory analyses, but at their existence the corresponding correction of fungicidal therapy is recommended. During treatment it is necessary to control changes of hematologic indicators, indicators of function of a liver, kidneys and other biochemical indicators.

At emergence of renal failures and a liver it is necessary to stop administration of drug.

Seldom or never at patients with serious associated diseases which received treatment flukonazoly using repeated doses at autopsy the changes testimonial of a liver necrosis came to light. These patients at the same time received a large amount of medicines some of which have hepatotoxic potential, and/or had associated diseases which could be the cause of a necrosis of a liver. In cases of a hepatotoxic of accurate interrelation between a total daily dose of a flukonazol, therapy duration, a floor or age of patients it was not revealed; after the therapy termination flukonazoly changes usually were reversible.

Effect of a flukonazol concerning inhibition of isoenzymes of P450 cytochrome. including CYP2C9 isoenzyme, can remain within 4-5 days after the end of treatment in connection with long TVl of a flukonazol.

The bigger risk of development of serious skin reactions at use of a flukonazol is characteristic of patients with AIDS. If the patient who receives treatment concerning an invasive/system fungal infection has a rash which is connected using a flukonazol, having character of violent damages and a multiformny exudative erythema, drug should be cancelled.

At patients with multiple factors of risk, such as organic changes of a myocardium, disturbances of water and electrolytic balance, treatment it has to be carried out under observation of the doctor and be followed by control of an ECG.

Influence on ability to driving of the car and to control of mechanisms
Flukonazol does not exert impact on ability to drive the car and to work with the equipment. However it is necessary to take possibility of dizziness and spasms into account.

Side effects:

The most frequent side effects observed during clinical trials of a flukonazol: headache, skin rash, abdominal pain, diarrhea and nausea. Frequency of development of side effects is classified according to recommendations of World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; seldom - not less than 0,01%, but less than 0,1%; very seldom - less than 0,01%.

From a nervous system: often - a headache; infrequently - dizziness, paresthesia, spasms, attacks, a tremor, sleeplessness, drowsiness.

From cardiovascular system: seldom - arrhythmia like "pirouette", lengthening of an interval of QT.
From the alimentary system: often - nausea vomiting, diarrhea, an abdominal pain; infrequently - anorexia, a lock, dyspepsia, a meteorism, dryness of mucous membranes oral полостиг taste disturbance.
From a liver and the bilious removing ways: often - clinically significant increase in activity of alaninaminotranspherase, aspartate aminotransferase, an alkaline phosphatase; infrequently - a cholestasia, hepatitis, jaundice, clinically significant increase in concentration of the general bilirubin in a blood plasma (0,3%), a hepatocellular necrosis; seldom - a liver failure, hepatitis.
From an urinary system: seldom - a renal failure. From bodies of a hemopoiesis: infrequently - anemia; seldom - a leukopenia, thrombocytopenia, a neutropenia, an agranulocytosis.
From integuments: infrequently - the increased perspiration, medicinal dermatitis; seldom - an alopecia; very seldom - acute generalized exanthematous and pustular rash.
From an acoustic organ and balance: infrequently - вертиго.
From a metabolism: seldom - a hypopotassemia, a gipertriglitseridemiya, a hypercholesterolemia.
From a musculoskeletal system: infrequently - a mialgiya.
Allergic reactions: often - rash; seldom - an anaphylaxis, a multiformny exudative erythema (including Stephens-Johnson's syndrome); very seldom - exfoliative dermatitis, a toxic epidermal necrolysis (Lyell's disease), a Quincke's disease, a face edema, a small tortoiseshell, a skin itch.
From an organism in general: infrequently - the general weakness, an indisposition, fever, increased fatigue.

At children side effects are shown more often than at adults. The most characteristic side reactions for children are irritability and anemia.

Interaction with other medicines:

Medicines contraindicated at a concomitant use of a flukonazol
At a concomitant use of a flukonazol and a tsizaprid there are disturbances of a cordial rhythm, including arrhythmia like "pirouette". At simultaneous use of a flukonazol in a dose of 400 mg/days and more with terfenadiny there is an increase in concentration of a terfenadin in a blood plasma that leads to increase in frequency of development of a heart consciousness, tachycardia, dizziness, a stethalgia and lengthening of an interval of QTc. This effect is absent at use of a flukonazol in a dose of 200 mg/days. In need of simultaneous use of a flukonazol and a terfenadin the dose of a flukonazol has to be less than 400 mg/days.

Astemizol in high doses at simultaneous use with flukonazoly leads to lengthening of an interval of QT, heavy ventricular arrhythmias, arrhythmia like "pirouette" and a cardiac standstill. At the simultaneous use of a flukonazol and other drugs increasing QT interval, patients have to be under fixed observation of the doctor because of risk of development of disturbances of a cordial rhythm.

The medicines changing metabolism of a flukonazol
Repeated use of a hydrochlorothiazide along with flukonazoly leads to increase in concentration of a flukonazol in plasma for 40%. This effect does not demand change of the mode of dosing of a flukonazol, but it should be considered. Simultaneous use of a flukonazol and rifampicin leads to decrease in AUC and T1/2 of a flukonazol by 25% and 20%, respectively. At such patients increase in a dose of a flukonazol is possible.

Medicines which metabolism changes at reception of a flukonazol
Flukonazol suppresses metabolism of a galofantrin. Flukonazol strengthens effects of methadone. AUC methadone increases at simultaneous use with flukonazoly by 35%. Flukonazol increases concentration of carbamazepine in a blood plasma at their simultaneous use.

At simultaneous use with flukonazoly AUC the fluvastatina increases to 200%. Extra care should be observed at simultaneous use of a flukonazol and other inhibitors of an isoenzyme CYP2C9 along with fluvastatiny. Use of a flukonazol leads to increase in concentration of a rifabutin in a blood plasma. At the patients receiving this combination development of a uveitis is possible. At simultaneous use of a rifabutin and flukonazol patients have to be under fixed observation of the doctor.

Flukonazol at simultaneous use with warfarin for men raises a prothrombin time for 12% in this connection development of bleedings is possible (hematomas, bleedings from a nose and digestive tract, a hamaturia, a melena). At the patients receiving indirect anticoagulants it is necessary to control a prothrombin time constantly.

Simultaneous use of a flukonazol and Phenytoinum can be followed by clinically significant increase in concentration of Phenytoinum in a blood plasma. In case of need simultaneous use of both drugs it is necessary to control concentration of Phenytoinum in a blood plasma and to carry out corresponding change of a dose of Phenytoinum. Simultaneous use of a flukonazol in a dose of 400 mg and alfentanil in a dose of 20 mkg/kg in/in increases AUC alfentanil twice and reduces its clearance by 55% because of CYP3A4 isoenzyme inhibition. At use of such combination it is necessary to change an alfentanil dose.

Intake of benzodiazepines of short action (midazolam) together with flukonazoly leads to increase in concentration of midazolam in a blood plasma and to strengthening of its psychomotor effects, and this influence is more expressed after reception of a flukonazol inside, than at its intravenous administration. At use of a flukonazol and need of the accompanying therapy by benzodiazepines it is necessary to reduce their dose. The risk of development of a myopathy and rabdomioliz increases at simultaneous use of inhibitors of GMG-KOA-reduktazy (azolovy antifungal drugs and statines, such as аторвастатин). In need of simultaneous use of these drugs it is necessary to control emergence of symptoms of a myopathy or rabdomioliz (muscular pain, muscular tension or muscular weakness), and also to control activity of a kreatinfosfokinaza in blood serum. Therapy by statines needs to be stopped at the expressed increase in activity of a kreatinfosfokinaza in blood serum or at establishment of the diagnosis of a myopathy or rabdomioliz, and also at suspicion of development of these complications.

Flukonazol increases concentration of a trimetreksat in a blood plasma that leads to oppression of marrow, disturbance of functions of a liver and kidneys, a digestive tract ulceration. If the combination of a flukonazol and a trimetreksat is vital, then it is necessary to exercise careful medical control of such patients. At simultaneous use with flukonazoly the increase in concentration of a zidovudine connected with delay of his metabolism is noted. Use of a flukonazol in a dose of 200 mg/days leads to dozozavisimy increase in AUC of a zidovudine from 20% to 74%.

Use of a flukonazol in a dose of 200 mg/days leads to slow increase in concentration of cyclosporine in a blood plasma at patients after transplantation of kidneys. Multiple dose of a flukonazol in a dose of 100 mg/days does not change concentration of cyclosporine in a blood plasma at patients after transplantation of marrow. At simultaneous use of a flukonazol and cyclosporine it is recommended to control concentration of cyclosporine in a blood plasma.

At cancellation of a flukonazol after long therapy along with Prednisonum careful control of function of adrenal glands is necessary.

Simultaneous use of a flukonazol in a dose of 100 and 200 mg and a takrolimusa leads to increase in serumal concentration of the last in 1,4 and 3,1 times, respectively. Development of anemia, a leukopenia, thrombocytopenia, a hypopotassemia, diarrhea is possible. Nephrotoxicity cases are described. The patients who are at the same time accepting such combinations of medicines should be observed carefully.

Flukonazol at simultaneous use leads to increase in T1/2 of hypoglycemic means for intake - sulphonylurea derivatives (Chlorproramidum, Glibenclamidum, a glipizid and Tolbutamidum). Patients with a diabetes mellitus can appoint jointly флуконазол and hypoglycemic means for intake - sulphonylurea derivatives, but at the same time it is necessary to control concentration of glucose in a blood plasma.

At simultaneous use of the combined oral contraceptives with flukonazoly in a dose of 50 mg it is not established essential change of concentration of ethinylestradiol, levonorgestrel and Norethisteronum in a blood plasma whereas at daily reception of 200 mg of a flukonazol of AUC ethinylestradiol and levonorgestrel increases by 40% and 24%, respectively, and at reception of 300 mg of a flukonazol of 1 time/week of AUC ethinylestradiol and Norethisteronum increases for 24% and 13%, respectively. Thus, repeated use of a flukonazol in the specified doses has no significant effect on efficiency of the combined oral contraceptives. Increase in concentration of amitriptyline in a blood plasma and development of toxic effects at simultaneous use with flukonazoly is possible. At simultaneous use of a flukonazol and nortriptilin, active metabolite of amitriptyline, increase in concentration of a nortriptilin in a blood plasma is possible. Due to the risk of development of toxic effects of amitriptyline it is recommended to control concentration of amitriptyline in a blood plasma and if necessary to change its dose.

At simultaneous use of a dose of 200 mg of a flukonazol there is a double increase in concentration of a tselekoksib in a blood plasma. It is supposed that similar interaction is connected with inhibition of metabolism of a tselekoksib in which CYP2C9 isoenzyme participates. At patients who receive флуконазол it is necessary to apply the minimum recommended doses of a tselekoksib.

Simultaneous use with flukonazoly leads to increase in concentration of a lozartan and decrease in concentration of its active metabolite in a blood plasma. Constant control of arterial pressure is necessary for patients.

Flukonazol increases concentration of theophylline in a blood plasma. At treatment flukonazoly the patients applying theophylline in high doses in case of symptoms of overdose of theophylline it is necessary to bring correction in the scheme of treatment. Some dihydropyridinic blockers of "slow" calcium channels, including nifedipine, исрадипин, никардипин, амлодипин and фелодипин, are metabolized with the participation of CYP3A4 isoenzyme. In literature there are messages on development of the expressed peripheral hypostases and/or increase in serumal concentration of blockers of "slow" calcium channels at simultaneous use of an itrakonazol and felodipin, isradipin or nifedipine. Similar interaction can be observed also at use of a flukonazol.

It is supposed that simultaneous use of a didanozin and flukonazol safely and renders small effect on pharmacokinetics and efficiency of a didanozin. However to control the response to therapy flukonazoly. It is recommended to reconsider a dose of a flukonazol before use of a didanozin.

Other interactions
Amphotericinum In is an antagonist of derivatives of an azol. Reception of a flukonazol inside along with food, Cimetidinum, antacids or after total radiation of an organism for the purpose of transplantation of marrow does not influence absorption of a flukonazol.

Contraindications:

Hypersensitivity to a flukonazol, other azolny antifungal drugs or to other components of this drug; simultaneous reception of a tsizaprid, terfenadin (against the background of constant reception of a flukonazol in a dose of 400 mg/days and more), Pimozidum, an astemizol, quinidine; the inborn or revealed lengthening of an interval of QT on an ECG, a concomitant use of the drugs extending QT interval (antiarrhytmic means of IA and the III classes); hereditary intolerance of a galactose, deficit of lactase and sprue of glucose galactose; pregnancy period; lactation period; the children's age is younger than 16 years.

With care
At an abnormal liver function, a renal failure, predisposition to development of arrhythmia, disturbance of electrolytic balance (a hypopotassemia, a hypomagnesiemia, a hypocalcemia), organic heart diseases, including cardiomyopathies, heavy chronic heart failure, clinically significant bradycardia, arrhythmia, emergence of rash against the background of use of a flukonazol for patients with a superficial fungal infection and invasive/system fungal infections, a concomitant use of a terfenadin and a flukonazol in a dose less than 400 mg/days.

Use during pregnancy and a lactation
Purpose of a flukonazol during the first trimester of pregnancy in doses did not lead less than 200 mg a day to increase in frequency of a fetotoksichnost, nevertheless, флуконазол has teratogenic effects.

Cases of multiple inborn defects at newborns whose mothers within 3 and more months received therapy flukonazoly in high doses (400-800 mg/days) concerning a coccidioidomycosis are described. Communication between these disturbances and reception of a flukonazol is not established.

It is necessary to avoid use of a flukonazol at pregnancy, except for hard cases and potentially life-threatening fungal infections of mother when the expected advantage of treatment for mother exceeds possible risk for a fruit. Women of childbearing age should use reliable methods of contraception during treatment and within 7 days after its termination, and before purpose of drug to be convinced of lack of pregnancy.

Flukonazol gets into breast milk in the concentration close to plasma. If use of drug is necessary, it is necessary to stop breastfeeding before treatment.

Overdose:

In one of cases of overdose of a flukonazol the 42-year-old patient infected with HIV after reception of 8200 mg of a flukonazol had hallucinations and paranoid behavior. The patient was hospitalized, his state was normalized during 48 h. Treatment: symptomatic therapy (including the supporting measures and a gastric lavage). The three-hour hemodialysis reduces concentration of a flukonazol in plasma approximately by 50%.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity of 5 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules of 50 mg, 100 mg, 150 mg.

Dosage of 50 mg: on 7 capsules in blisters from an aluminum foil / PVC / PVDH; 1 blister with the application instruction in a cardboard pack.

Dosage of 100 mg: on 7 capsules in blisters from an aluminum foil / PVC / PVDH; 1 blister with the application instruction in a cardboard pack; on 10 capsules in blisters from an aluminum foil / PVC / PVDH, 1, 3, 6 or 10 blisters with the application instruction in a cardboard pack.

Dosage of 150 mg: on 1 capsule in blisters from an aluminum foil / PVC / PVDH, 1 blister with the application instruction in a cardboard pack.