Flukonazol

General characteristics. Structure:

Active ingredient: 100 mg, 150 mg or 200 mg of a flukonazol in 1 capsule.

Pharmacological properties:

Pharmacodynamics. P450 cytochrome - dependent enzymes blocks a row and vysokoselektivno inhibits synthesis of sterol in cellular membranes of mushrooms. It is effective at the infections caused by fungi of the sort Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp., and also at the infections caused by activators Blastomyces dermatitidis, Coccidioides immitis ihistoplasma capsulatum.

Pharmacokinetic characteristics of a flukonazol are similar at in introduction and at intake.

After intake it is well soaked up from a GIT. Bioavailability makes 90%, meal does not influence absorption. Linkng with proteins of plasma — 11–12%. Cmax  and AUC are proportional to a dose. Cmax  is reached in 1–2 h after reception. Equilibrium concentration — in techeniye5-10 days of treatment (at reception of 50-400 mg of 1 times a day). Introduction in the first day of treatment of the shock dose twice exceeding a usual daily dose allows to reach the level close to equilibrium concentration, by second day. The seeming volume of distribution approaches the general content of water in an organism. Well gets into all biological liquids of an organism, passes through GEB. At the meningitis caused by fungi, the level of a flukonazol in liquor reaches about 80% of level in plasma. At healthy volunteers concentration of a flukonazol was equal in saliva or slightly exceeded its level in plasma regardless of a dose, a way and duration of introduction. Patients with bronchiectasias have a concentration of a flukonazol in a phlegm in 4 and 24 h after a single peroral dose of 150 mg was similar to plasma. After reception of a single peroral dose of 150 mg the ratio of concentration of a flukonazol vaginal fabric / plasma made 0,94–1,14 during the first 48 h (n=27), ratio vaginal liquid / plasma — 0,36–0,71 during the first 72 h (n=14). The ratio of concentration of a flukonazol urine/plasma and normal skin / plasma reached 10.

It is removed generally by kidneys, at healthy volunteers of 80% of a flukonazol about 11% — in the form of metabolites are excreted in not changed look. T1/2  is about 30 h (in the range of 20-50 h). The pharmacokinetics of a flukonazol significantly depends on function of kidneys. T1/2  is inversely proportional to clearance of creatinine.

At reception of a flukonazol by healthy volunteers in doses from 200 to 400 mg once within 14 days the insignificant effect on concentration of testosterone, endogenous corticosteroids and AKTG-stimulirovanny the kortizolovy answer was noted. At reception on 50 mg a day флуконазол did not change concentration of testosterone in blood at men and the maintenance of steroids at women of childbearing age.

Carcinogenicity, mutagenicity, influence on fertility. The evidence of carcinogenicity of a flukonazol in researches at the mice and rats receiving it inside within 24 months in doses 2,5 is not obtained; 5 and 10 mg/kg/days (approximately by 2–7 times exceeding the recommended doses for the person). At males of rats at doses of 5 and 10 mg/kg/days increase in frequency of developing of hepatocellular adenomas was noted.

The mutagenicity of a flukonazol in a number of in vitro tests and in vivo is not revealed.

Influence on fertility of males and females of rats at daily peroral introduction of doses of 5, 10 either 20 mg/kg or parenteral administration of doses of 5, 25 or 75 mg/kg is noted though at peroral doses of 20 mg/kg the small delay of the beginning of childbirth was noted. In perinatal researches at in introduction to rats of doses of a flukonazol of 5, 20 and 40 mg/kg several females receiving doses of 20 and 40 mg/kg (approximately v5-15raz above recommended for the person), had complicated childbirth and long. This effect was not noted at doses 5 mg/kg. Disturbances of childbirth were followed by small increase in frequency of appearance of mortinatus cubs and decrease in neonatal survival. Influence on childbirth at rats will be coordinated with specific is oestrogenic - the reducing effect caused by high doses of a flukonazol. Similar hormonal changes are not found in the women receiving флуконазол.

Pregnancy. Teratogenic effects. In two researches at oral administration of a flukonazol at pregnant rabbits in the period of an organogenesis at doses of 5, 10, 20, 25 and 75 mg/kg disturbance of an increase of body weight of animals at all doses was observed and abortions at a dose of 75 mg/kg (is about 20-60 times higher than the recommended doses for the person), at the same time adverse fetalis disturbances were not noted. In several researches in which флуконазол it was applied inside at pregnant rats in the period of an organogenesis disturbances of an increase of body weight and placental weight were increased at a dose 25 mg/kg. At doses of 5 or 10 mg/kg of fetalis disturbances it was not noted; at doses of 25 and 50 mg/kg and above increase in number of anatomic changes at a fruit (additional edges, a pyelectasia), an ossification delay was noted. When using doses in the range from 80 mg/kg (is about 20-60 times higher than the recommended doses for the person) the embrioletalnost and fetalis disturbances, including wavy edges, a wolf mouth and disturbances of kranio-facial ossification increased to 320 mg/kg at rats. These effects will be coordinated with suppression of synthesis of estrogen at rats and can be result of the known influence of the lowered level of estrogen on the course of pregnancy, an organogenesis and childbirth.

Indications to use:

Cryptococcosis: cryptococcal meningitis, infections of skin and lungs; prevention of a recurrence of a cryptococcosis at patients with AIDS; generalized candidiasis: a kandidemiya, the disseminated candidiasis and other forms of invasive candidosis infections (defeat of a peritoneum, endocardium, an eye, respiratory and urinary tract); candidiasis of mucous membranes of an oral cavity and throat, gullet, bronchopulmonary candidiasis, kandiduriya, candidiases of skin and mucous membranes, the atrophic candidiasis of an oral cavity (connected with carrying dentures), prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS; genital candidiasis: vaginal (acute or recurrent), including prevention of a recurrence, a candidosis balanitis; prevention and treatment of fungal infections at malignant new growths (treatment by cytostatics and/or radiation therapy), antibiotic treatment, treatment by immunodepressants, after transplantation; skin mycoses (stop, bodies, inguinal area), chromophytosis, onychomycosis, skin candidiasis; deep local mycoses (кокцидиомикоз, паракокцидиомикоз, a sporotrichosis, histoplasmosis) at patients with undisturbed immunity.

Route of administration and doses:

Inside, in / century. The dose, a way of introduction, duration of a course of treatment are defined individually depending on indications, a condition of sick, clinical and mycologic effect. The daily dose depends on character and weight of an infection. At children the daily dose should not exceed the maximum daily dose for adults. At transfer of the patient with in/in introductions of a flukonazol on intake and vice versa there is no need to change a daily dose.

The adult at a cryptococcosis and generalized candidiasis — in/in, inside, 400 mg in the 1st day, then on 200–400 mg a day; at oropharyngeal candidiasis — inside, 50–100 mg a day in techeniye7-14dny; at vaginal candidiasis — inside, 150 mg once, at a chronic form — once a month on 150 mg in techeniye4-12mes; at mycoses — on 150 mg once a week.

To children at generalized candidiasis — 6–12 mg/kg/days, at candidiasis of mucous membranes — 3–6 mg/kg/days, for prevention of fungal infections — 3–12 mg/kg/days.

Features of use:

Use at pregnancy and feeding by a breast. At pregnancy it is possible only at life-threatening heavy infections if the expected effect of therapy exceeds potential risk for a fruit (adequate and strictly controlled researches of safety of use for pregnant women were not conducted). Babies whose mothers within 3 months also were more treated by high doses of a flukonazol — 400–800 mg/days concerning a coccidioidomycosis have messages on various inborn disturbances though relationship of cause and effect of these cases with reception of a flukonazol is not clear.

Category of action on a fruit on FDA — C. For the period of treatment it is necessary to stop breastfeeding (concentration of a flukonazol in breast milk are comparable with plasma).

At patients with a renal failure (at creatinine Cl less than 50 ml/min.) the mode of dosing should be corrected; at a single dose change of a dose is not required.

The newborn in the first 2 weeks of life appoint in the same dose (mg/kg), as for children of more advanced age, but with an interval of 72 h; at the age of 3–4 weeks — in the same dose with an interval of 48 h.

During treatment it is necessary to control carefully indicators of peripheral blood and function of a liver. At emergence of signs of a hepatotoxic, rash, violent changes, a mnogoformny erythema therapy should be cancelled.

Special instructions. Treatment flukonazoly can be begun before obtaining results of crops and other laboratory analyses, but after obtaining results of these researches therapy needs to be changed as appropriate.

Treatment needs to be continued before emergence of clinical/hematologic remission (an exception acute vulval candidiasis is). The premature termination of treatment leads to a recurrence.

Side effects:

At the patients receiving a single dose at vaginal candidiasis. When performing comparative clinical trials in the USA at the patients with vaginal candidiasis (n=448) receiving a single dose of a flukonazol of 150 mg, the total frequency of the side effects which are perhaps connected with drug intake made 26%; at the patients receiving drug of comparison (n=448) – 16%. The most frequent side effects connected with reception of a flukonazol were: headache (13%), nausea (7%), abdominal pain (6%), diarrhea (3%), dyspepsia (1%), dizziness (1%), food faddism (1%). The majority of side effects was weak or moderate degree of manifestation. Very seldom in market researches the angioedema and anaphylactic reactions were noted.

At the patients receiving repeated doses at other infections. In clinical tests approximately at 16% from 4048 patients, treated flukonazoly within 7 and more days, side reactions were noted. Treatment was stopped because of emergence of adverse effects at 1,5%, because of deviations in laboratory tests — at 1,3% of patients.

During treatment flukonazoly clinically expressed side effects were noted at HIV-positive patients (21%), unlike ne-VICh-infitsirovannykh more often (13%). The number of the patients who stopped treatment because of emergence of adverse effects was similar in both groups (1,5%).

Side effects which were observed in clinical tests at treatment flukonazoly within 7 and more days more than in 1% of cases and were connected with drug intake (n=4048): nausea (3,7%), headache (1,9%), skin rash (1,8%), vomiting (1,7%), abdominal pain (1,7%) and diarrhea (1,5%).

Side effects which communication with treatment flukonazoly is probable: hepatotoxic, immunological reactions.

Hepatotoxic. The integrated data of clinical tests and marketing experience show that treatment flukonazoly is followed by exceptional cases of serious toxic reactions from a liver, including a lethal outcome. The obvious interrelation of the flukonazol-associated hepatotoxic with the general day dose, therapy duration, a sex, age of patients is not revealed. The hepatotoxic action of a flukonazol usually (but not always) is reversible, symptoms disappear after the therapy termination. In order to avoid serious reactions from a liver it is necessary to observe carefully patients at whom during therapy flukonazy disturbances of functional hepatic tests are revealed. Treatment flukonazoly has to be stopped at emergence of clinically expressed symptoms of the developing liver disease which can be connected with treatment flukonazoly.

Reactions from a liver can have different expressiveness: from small tranzitorny increase in level of hepatic transaminases to clinically expressed hepatitis, a cholestasia, a fulminantny liver failure, including a lethal outcome. The patients who are suffering from a serious basic disease (AIDS, tumoral diseases) and often receiving polymedicamentous therapy had cases of fatal hepatic reactions in mainly.

In two comparative tests of assessment of efficiency of a flukonazol concerning prevention of a recurrence of cryptococcal meningitis statistically significant increase in a median of levels of nuclear heating plant from basic was revealed. Increase in level of transaminases of serum more чемв 8 times was higher than an upper limit of norm it is noted approximately at 1% of patients, treated flukonazoly. These cases were observed at patients with a serious basic disease (AIDS, malignant new growths), the majority of which received the multiple accompanying medicinal therapy, including many HP with the known hepatotoxic. Frequency of increase in level of transaminases was higher at the patients receiving along with flukonazoly one or more of the following means: Rifampinum, Phenytoinum, an isoniazid, valproic acid, peroral hypoglycemic means – sulphonylurea derivatives.

Immunological reactions: it was reported about exceptional cases of an anaphylaxis.

Side effects which connection with treatment flukonazoly is not established.

From TsNS: spasms.

Dermatological: exfoliative skin diseases, including Stephens-Johnson's syndrome and a toxic epidermal necrolysis; alopecia.

Exfoliative skin diseases at treatment flukonazoly developed seldom, at patients with serious basic diseases (AIDS, tumoral diseases) seldom they had a fatal outcome. If against the background of treatment flukonazoly skin symptoms are shown, careful observation of the patient is required and at increase of symptomatology treatment flukonazoly needs to be stopped.

Gematopoetichesky and lymphatic: a leukopenia, including a neutropenia and an agranulocytosis, thrombocytopenia.

Metabolic: hypercholesterolemia, gipertriglitseridemiya, hypopotassemia.

The side effects observed at children. When carrying out clinical tests of the Phase 2 and 3 in the USA and Europe at 577 patients at the age of 1 день−17 years, treated flukonazoly in doses to 15 mg/kg/days up to 1616 days, side effects at children were observed in 13% of cases; at the patients receiving drug of comparison (n=451) — in 9% of cases. The following was the most cumulative noted side effects: vomiting (5,4%), abdominal pain (2,8%), nausea (2,3%), diarrhea (2,1%). Treatment was stopped because of emergence of adverse effects at 2,3% of patients, because of deviations in laboratory tests (in most cases — increase in levels of transaminases and an alkaline phosphatase) — at 1,4% of patients.

Interaction with other medicines:

Flukonazol increases T1/2  from plasma of peroral hypoglycemic drugs — sulphonylurea derivatives (clinically expressed hypoglycemia is possible). Increases concentration of Phenytoinum (in case of need simultaneous use of both HP it is necessary to control concentration of Phenytoinum and as appropriate to correct its dose for the purpose of ensuring therapeutic concentration in serum). Against the background of a flukonazol increase (biotransformation) serumal concentration of theophylline is slowed down (it is necessary to carry out careful monitoring of concentration of theophylline to blood and if necessary to correct therapy as appropriate). At simultaneous use of a zidovudine with flukonazoly increase in Cmax  of a zidovudine for 84%, AUC — for 74% is noted, T1/2  is prolonged approximately for 128%; increase in side effects of a zidovudine is possible (the zidovudine dose decline can be required). Flukonazol raises AUC of a sakvinavir approximately for 50%, Cmax  — approximately for 55% and reduces clearance of a sakvinavir approximately by 50% (dose adjustment of a sakvinavir can be required).

Flukonazol increases plasma concentration of a sirolimus presumably because of inhibition of metabolism of the sirolimus mediated by CYP3A4 and P-a glycoprotein (at simultaneous use dose adjustment of a sirolimus can be required).

Flukonazol can significantly increase cyclosporine level in blood at patients with transplantation of a kidney with or without renal failures (monitoring of concentration of cyclosporine and level of creatinine in blood is necessary).

At combined use of a flukonazol and anticoagulants of coumarinic type PV in this connection development of bleedings is possible can be extended (hematomas, bleedings from a nose and a GIT, a hamaturia and a melena); careful monitoring of PV is recommended, change of a dose of warfarin can be required. Rifampicin increases metabolism of a flukonazol: AUC decreases by 25%, T1/2  — for 20% (it is necessary to provide a possibility of increase in a dose of a flukonazol).

At reception of a flukonazol (100 mg) together with a hydrochlorothiazide (50 mg) within 10 days the level of a flukonazol in a blood plasma of healthy volunteers (n=13) increased approximately by 40%, the renal clearance decreased by 30%.

At simultaneous use of a flukonazol and rifabutin serumal concentration of a rifabutin increase. There are messages on development of a uveitis. The patients who are at the same time receiving рифабутин and флуконазол need to be observed carefully.

Flukonazol can increase system exposure of NPVS which are metabolized by means of CYP2C9 (including Naproxenum, to lornoksika, meloksika, diclofenac); frequent observation of patients for early detection of side effects and NPVS-oposredovannoy is recommended to toxicity; correction of a dose of NPVS can be necessary.

At a concomitant use of a flukonazol (200 mg daily) and a tselekoksiba (200 mg) of Cmaxuvelichivalas for 68%, AUC — for 134%; at joint reception reduction of a dose of a tselekoksib half can be necessary.

Use of a flukonazol along with the HP which are metabolized with participation of system of enzymes of P450 cytochrome (including цизаприд, астемизол, quinidine) can lead to increase in serumal levels of these means (in the absence of exact information it is necessary to be careful and carefully to watch a condition of patients). Considering developing of serious arrhythmias at the patients receiving other azolny antifungal means in combination with terfenadiny at simultaneous use of a flukonazol and terfenadin careful observation of patients is necessary.

Against the background of a flukonazol biotransformation of a tsizaprid is slowed down, the risk of cardiovascular disturbances, including fatal arrhythmias (Bouveret's ventricular disease) increases. In controlled researches it is shown that use of a flukonazol in a dose of 200 mg of 1 times a day and a tsizaprid in a dose of 20 mg 4 times a day within 5 days leads to the expressed increase in plasma concentration of a tsizaprid and increase in an interval of QT at an ECG. The concomitant use of a tsizaprid and a flukonazol is contraindicated (see. "Contraindications").

Flukonazol can increase system influence of some BKK (nifedipine, исрадипин, амлодипин, фелодипин) which are metabolized with participation of CYP3A4. The patients who are at the same time receiving флуконазол and nifedipine, it is recommended to observe carefully in connection with increase in risk of emergence of side effects.

Flukonazol inhibits metabolism of carbamazepine and increases carbamazepine level in blood serum (by 30%), the risk of development of toxicity of carbamazepine increases; change of a dose of carbamazepine can be necessary.

Flukonazol can increase serumal concentration of orally accepted takrolimus (risk of nephrotoxicity); at joint appointment change of a dosage of a takrolimus can be required. Significant pharmacokinetic changes at use of a takrolimus in / were not noted century.

After midazolam intake флуконазол significantly increases concentration of midazolam and psychomotor effects; this influence is more expressed after reception of a flukonazol inside, than at its use in / century. In need of the accompanying therapy by benzodiazepines of short action at the patients accepting флуконазол the benzodiazepine dose decline can be required.

Flukonazol increases effect of amitriptyline; measurement of level of amitriptyline / нортриптилина at the beginning of a combination therapy is desirable and in 1 week, if necessary it is necessary to adjust an amitriptyline dose.

There is a message on development in the patient receiving Prednisonum after transplantation of a liver, acute insufficiency of bark of adrenal glands in 3 months after the end of therapy flukonazoly. Presumably, the end of therapy flukonazoly (CYP3A4 inhibitor) caused increase in activity of this isoenzyme that led to increase in metabolism of Prednisonum. At the patients who are on long therapy flukonazoly and Prednisonum, it is necessary to monitorirovat carefully function of bark of adrenal glands after the end of therapy flukonazoly.

Antacids do not influence absorption of a flukonazol.

Solution for infusions is compatible to solutions of 20% of glucose, Ringer, Hartman, chloride potassium in glucose, sodium of bicarbonate of 4,2%, isotonic solution of sodium of chloride.

Contraindications:

Hypersensitivity, concomitant use of a terfenadin at repeated use of doses of a flukonazol of 400 mg and above; combined use with HP which prolong an interval of QT and are metabolized by means of CYP3A4 (such as цизаприд, астемизол, quinidine) — see. "Interaction".

Restrictions to use. The known hypersensitivity to other derivatives of an azol since there are no data of rather cross hypersensitivity between flukonazoly and other azolny antifungal means (it is necessary to be careful).

Overdose:

Symptoms: nausea, vomiting, diarrhea, in hard cases — spasms.

Treatment: a gastric lavage, an artificial diuresis, a hemodialysis (the three-hour hemodialysis reduces concentration of drug in plasma approximately by 50%), symptomatic therapy.

The 42-year-old HIV-positive patient has one message on overdose of a flukonazol (8200 mg inside) with development of hallucinations and paranoid behavior. The patient was hospitalized, and his state was normalized during 48 h.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity  3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Mg capsules 100, 150 and 200. On 10 capsules in each blister, on one blister together with the application instruction in cardboard packaging.