Itrakonazol of 100 mg

General characteristics. Structure:

Active ingredient: итраконазол - 0,100 g, excipients: a gipromelloza (a gidroksipropilmetiltsellyuloz of E-5) - 0,1472 g, butylmethacrylate, dimethylaminoethylmethacrylate and methylmethacrylate copolymer [1:2:1] (эудрагид E-100) - 0,0046 g, sucrose (sugar) - 0,2070 g.

Structure of a cover of capsules case: gelatin, titanium dioxide (Е 171), azoruby (carmoisin) E 122; lid: gelatin, titanium dioxide (Е 171), indigo carmine - F D&C Blue 2 (Е 132).

Description: solid gelatin capsules of N0 opaque pink color with a lid of blue color. Contents of capsules - spherical microgranules (pellets) from white till cream color.

Pharmacological properties:

Pharmacodynamics. Synthetic antifungal broad-spectrum agent. Derivative triazole. Suppresses synthesis of ergosterol of a cellular membrane of mushrooms. It is active concerning dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), barmy mushrooms of Candida spp. (including Candida albicans, Candida parapsilosis), mold mushrooms (Cryptococcus neoformans, Aspergillus spp., Trichosporon spp., Geotrichum spp., Penicillium marneffei, Pseudallescheria boydii, Histoplasma spp., Coccidioides immitis, Paracoccidioides braziliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatidis), Malassezia spp. Some strains can be steady: Candida glabrata, Candida krusei, Candida tropicalis, Absidia spp., Fusarium spp., Mucor spp., Rhizomucor spp., Rhizopus spp., Scedosporium proliferans, Scopulariopsis spp. Efficiency of treatment is estimated in 2-4 weeks after the therapy termination (at mycoses), in 6-9 months - at onychomycoses (in process of change of nails).

Pharmacokinetics. It is soaked up from the digestive tract (DT) rather fully. Reception of an itrakonazol in capsules right after food increases bioavailability. Reception in the form of solution on an empty stomach leads it to higher speed of achievement of the maximum concentration (Cmax) and bigger size of concentration of an equilibrium phase (Css) in comparison with reception after food (for 25%). Time of achievement of the maximum concentration (TCmax) at reception of capsules - about 3-4 h Css at reception of 100 mg of drug of 1 times a day - 0,4 mkg/ml; at reception of 200 mg of 1 times a day - 1,1 mkg/ml, 200 mg 2 times a day - 2 mkg/ml. TCmax at reception of solution is about 2 h at reception on an empty stomach and 5 h - after food. Time of approach of Css in plasma at prolonged use - 1-2 weeks. Communication with proteins of plasma - 99,8%. Well gets into fabrics and bodies (including into a mucous membrane of a vagina), contains in a secret grease and sweat glands. Concentration of an itrakonazol in lungs, kidneys, a liver, bones, a stomach, a spleen, skeletal muscles by 2-3 times exceeds its concentration in plasma; in the fabrics containing a keratin - by 4 times. Therapeutic concentration of an itrakonazol in skin remains within 2-4 weeks after the termination 4 week courses of treatment. Therapeutic concentration in a keratin of nails is reached in 1 week after an initiation of treatment and 3 monthly courses of treatment remain within 6 months after end. Low concentration are defined in grease and sweat glands of skin. The gidroksiitrakonazola is metabolized in a liver with formation of active metabolites, including. Is inhibitor of isoenzymes CYP3A4, CYP3A5 and CYP3A7. Removal from plasma - two-phase: kidneys within 1 week (35% in the form of metabolites, 0,03% - in not changed look) and through intestines (3-18% in not changed look). An elimination half-life (T1/2) - 1-1,5 days. Is not removed when carrying out dialysis.

Indications to use:

Vulvovaginal candidiasis; a dermatomycosis, multi-colored deprive, candidiasis of a mucous membrane of an oral cavity, a keratomycosis; the onychomycosis caused by dermatophytes or drozhzhepodobny mushrooms; system mycoses - a system aspergillosis or candidiasis, a cryptococcosis (including cryptococcal meningitis) at immunokompromitirovanny persons and a cryptococcosis of the central nervous system irrespective of the immune status at inefficiency of therapy of the 1st line; histoplasmosis, zymonematosis, sporotrichosis, paracoccidioidosis; the other seldom found system and tropical mycoses.

Route of administration and doses:

Inside. Right after food. Capsules are swallowed entirely. Drug removal итраконазол from skin and nail fabric is carried out more slowly, than from plasma. Thus, optimum clinical and mycologic effects are reached in 2-4 weeks after the end of treatment at infections of skin and in 6-9 months after the end of treatment of nail infections. Duration of treatment can be corrected depending on a clinical picture of treatment: - at vulvovaginal candidiasis - 200 mg 2 times a day within 1 day or 200 mg of 1 times a day within 3 days; - at dermatomycoses - 200 mg of 1 times a day within 7 days or 100 mg of 1 times a day within 15 days; - defeats of the high-keratinized sites of skin (a dermatofitiya of feet and brushes) - 200 mg 2 times a day within 7 days or 100 mg of 1 times a day within 30 days; - at a chromophytosis - 200 mg of 1 times days within 7 days; - at candidiasis of a mucous membrane of an oral cavity - 100 mg of 1 times a day within 15 days (in certain cases at immunokompromitirovanny persons bioavailability of an itrakonazol can decrease that sometimes demands doubling of a dose); - at keratomycoses - 200 mg of 1 times a day within 21 days (duration of treatment depends on the clinical answer); - at an onychomycosis - 200 mg of 1 times a day within 3 months or 200 mg 2 times a day within 1 week on a course; - at damage of nails standing (irrespective of existence of damage of nails on hands) conduct 3 courses with an interval of 3 weeks. At damage of nails only on hands conduct 2 courses with an interval of 3 weeks; - elimination of an itrakonazol from skin and nails slow; the optimum clinical answer at dermatomycoses is reached in 2-4 months after completion of treatment, at onychomycoses - 6-9 months; - at a system aspergillosis - 200 mg/days within 2-5 months; during the progressing and dissimination of a disease the dose is increased to 200 mg by 2 times a day; - at system candidiasis - 100-200 mg of 1 times a day within 3 weeks - 7 months, during the progressing and dissimination of a disease increase a dose to 200 mg 2 times a day; - at a system cryptococcosis without symptoms of meningitis - 200 mg of 1 times a day within 2-12 months. At cryptococcal meningitis - 200 mg 2 times a day within 2-12 months. - treatment of histoplasmosis begin with 200 mg of 1 times a day, a maintenance dose - 200 mg 2 times a day within 8 months; - at a zymonematosis - 100 mg of 1 times a day, a maintenance dose - 200 mg 2 times a day within 6 months; - at a sporotrichosis - 100 mg of 1 times a day within 3 months; - at a paracoccidioidosis - 100 mg of 1 times a day within 6 months; - at chromomycosis - 100-200 mg of 1 times a day within 6 months; - to children appoint if the expected advantage exceeds potential risk.

Features of use:

- The women of childbearing age accepting Itrakonazol need to use reliable methods of contraception throughout all course of treatment up to approach of the first periods after its end.

- It is revealed what итраконазол possesses a negative inotropic effect. At a concomitant use of an itrakonazol and blockers of calcium channels which can render the same effect it is necessary to be careful. It was reported about the cases of chronic heart failure connected with Itrakonazol's reception. Itrakonazol patients should not accept with chronic heart failure or with existence of this disease in the anamnesis except for cases when the possible advantage considerably surpasses potential risk. At individual assessment of a ratio of advantage and risk it is necessary to take such factors as gravity of indications, the mode of dosing and individual risk factors of developing of chronic heart failure into account. Risk factors include existence of heart diseases, such as coronary heart disease or defeats of valves; serious diseases of lungs, such as obstructive damages of lungs; the renal failure or other diseases which are followed by hypostases. Such patients need to be informed on signs and symptoms of congestive heart failure. Treatment has to be carried out with care, at the same time it is necessary to monitorirovat the patient regarding emergence of symptoms of congestive heart failure. At their emergence Itrakonazol's reception needs to be stopped.

- At the lowered acidity of a stomach: at this state absorption of an itrakonazol from capsules is broken. To the patients accepting antiacid drugs (for example, aluminum hydroxide), it is recommended to use them not earlier than in 2 hours after reception of capsules of Itrakonazol. To patients with an achlorhydria or applying blockers of H2-histamine receptors and inhibitors of a proton pomp, it is recommended to accept Itrakonazol's capsules with the drinks containing Coca.

- Seldom or never at Itrakonazol's use crushing toxic damage of a liver, including cases of an acute liver failure with a lethal outcome developed. In most cases it was noted at the patients who already had liver diseases, at patients, with other serious illness, receiving therapy itrakonazoly according to system indications, and also at the patients receiving other medicines possessing a hepatotoxic action. At some patients obvious risk factors concerning damage of a liver did not come to light. Several such cases arose in the first month of therapy, and some - in the first week of treatment. In this regard it is regularly recommended to control function of a liver at the patients receiving therapy itrakonazoly. Patients should be warned about need to contact immediately the doctor in case of the symptoms assuming developing of hepatitis namely: anorexias, nausea, vomitings, weaknesses, abdominal pains and darkenings of urine. In a case emergence of such symptoms it is necessary to stop immediately therapy and to conduct a research of function of a liver. To patients with the increased concentration of enzymes or a disease of a liver in an active phase, or at the postponed toxic damage of a liver at reception of other drugs it is not necessary to appoint treatment Itrakonazoly unless the expected advantage justifies risk of damage of a liver. In these cases it is necessary to control concentration of enzymes during treatment.

- Abnormal liver functions: итраконазол it is metabolized preferential in a liver. As at patients with abnormal liver functions the full elimination half-life of an itrakonazol is a little increased, it is recommended to exercise control of concentration of an itrakonazol in plasma and if necessary to adjust a drug dose.

- Renal failures: As at patients with a renal failure the full elimination half-life of an itrakonazol is a little increased, it is recommended to exercise control of concentration of an itrakonazol in plasma and if necessary to adjust a drug dose. - Patients with an immunodeficiency: bioavailability of an itrakonazal at oral administration can be reduced at some patients with the broken immunity, for example, at patients with a neutropenia, patients with AIDS or undergone an operation on organ transplantation. - Patients with the system fungal infections posing a threat of life: owing to pharmacokinetic characteristics Itrakonazol in the form of capsules is not recommended to start treatment of the system mycoses posing a threat for life of patients.

- Patients with AIDS. - The attending physician has to estimate need of purpose of a maintenance therapy the sick AIDS which was earlier receiving treatment concerning system fungal infections, for example, of a sporotrichosis, a zymonematosis, histoplasmosis or a cryptococcosis (both meningeal, and not meningeal) which have a risk of a recurrence.

- Clinical data on use of capsules Itrakonazol in pediatric practice are limited. Itrakonazol children should not appoint capsules, except for cases when the expected advantage exceeds possible risk.

- Treatment should be stopped when developing peripheral neuropathy which can be connected with reception of capsules of Itrakonazol. - There are no data on cross hypersensitivity to Itrakonazol and other azolovy antifungal drugs.

Side effects:

From digestive tract: dyspepsia (nausea, vomiting, diarrhea, lock, loss of appetite), abdominal pain.

From genamo-biliary system: reversible increase in enzymes, hepatitis, seldom or never at Itrakonazol's use developed crushing toxic damage of a liver, including cases of an acute liver failure with a lethal outcome.

From a nervous system: headache, dizziness, peripheral neuropathy.

From immune system: anaphylactic, anaphylactoid and allergic reactions.

From integuments: seldom or never - a multiformny exudative erythema (Stephens-Johnson's syndrome), skin rash, a skin itch, a small tortoiseshell, a Quincke's disease, an alopecia, a photosensitivity.

Others: disturbances of a menstrual cycle, hypopotassemia, edematous syndrome, chronic heart failure and fluid lungs.

Interaction with other medicines:

1. The medicines exerting impact on absorption of an itrakonazol. The medicines reducing acidity of a stomach reduce absorption of an itrakonazol that is connected with solubility of covers of capsules. 2. The medicines exerting impact on metabolism of an itrakonazol. Itrakonazol is generally metabolized by CYP3A4 isoenzyme. Interaction of an itrakonazol with rifampicin, rifabutiny and Phenytoinum, the being powerful inductors of an isoenzyme CYP3A4 was studied. By a research it was established that in these cases bioavailability of an itrakonazol and gidroksiitrakonazol considerably decreases that leads to essential reduction of efficiency of drug. Simultaneous use of an itrakonazol with these drugs which are potential inductors of microsomal enzymes of a liver is not recommended. Interaction researches with other inductors of microsomal enzymes of a liver, such as carbamazepine, phenobarbital and isoniazid, were not conducted, however, similar results it is possible to assume. Powerful inhibitors of an isoenzyme CYP3A4, such as ритонавир, индинавир, кларитромицин and erythromycin, can increase bioavailability of an itrakonazol. 3. Influence of an itrakonazol on metabolism of other medicines. Itrakonazol can inhibit metabolism of the drugs split by CYP3A4 isoenzyme. Strengthening or prolongation of their action including side effects can be result of it. Before reception of the accompanying medicines, it is necessary to consult with the attending physician concerning the ways of metabolism of this drug specified in the instruction on a medical use. After the termination of treatment of concentration of an itrakonazol in plasma decrease gradually depending on a dose and duration of treatment (see the section Pharmacokinetics). It needs to be taken into account at discussion of the migrating effect of an itrakonazol to the accompanying medicines. Examples of such drugs are: Drugs which it is impossible to appoint along with itrakonazoly: - терфенадин, астемизол, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, левацетилметадол, сертиндол - combined use of these medicines with itrakonazoly can cause increase in concentration of these substances in plasma and increase risk of lengthening of an interval of QT and in rare instances - emergence of a ciliary arrhythmia of ventricles (torsade des pointes), - metaboliziruyemy CYP3A4 isoenzyme inhibitors of GMG-KOA reductase such as симвастатин and ловастатин, - midazolam for intake and to triazoles, - ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine, - blockers of calcium channels - in addition to the possible pharmacokinetic interaction connected with the general way of metabolism with participation of an isoenzyme of CYP3A4, blockers of calcium channels can render a negative inotropic effect which amplifies at a concomitant use with itrakonazoly. Drugs at which purpose it is necessary to watch their concentration in plasma, action, side effects. In case of co-administration with itrakonazoly a dose of these drugs if it is necessary, it is necessary to reduce. - Indirect anticoagulants; - HIV protease inhibitors, such, as ритонавир, индинавир, саквинавир; - Some antineoplastic drugs, such as alkaloids of a periwinkle pink, бусульфан, dotsetakset, триметрексат; - Metaboliziruyemye CYP3A4 isoenzyme blockers of calcium channels, such as verapamil and derivatives of dihydropyridine; - Some immunosuppressive means: cyclosporine, такролимус, сиролимус (also known as рапамицин); - Some metaboliziruyemy CYP3A4 isoenzyme inhibitors of GMG-KOA reductase such, as аторвастатин; - Some glucocorticosteroids, such, as будесонид, dexamethasone and Methylprednisolonum; - Other drugs: digoxin, carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, midazolam for intravenous administration, рифабутин, эбастин, ребоксетин, цилостазол, дизолирамид, элетриптан, галофантрин, репаглинид. Interaction between itrakonazoly and a zidovudine and fluvastatiny is not revealed. Influence of an itrakonazol on metabolism of ethinylestradiol and Norethisteronum was not noted. 4. Influence on communication by proteins of plasma. The researches in vitro showed lack of interaction between itrakonazoly and such drugs as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum and Sulfamethazinum at linkng with proteins of plasma.

Contraindications:

Hypersensitivity, chronic heart failure, including in the anamnesis (except for therapy of zhizneugrozhayushchy states); a concomitant use of substrates of an isoenzyme of CYP3A4 extending QT interval (астемизол, bepridit, цизаприд, дофетилид, левацетилметадол, мизоластин, Pimozidum, quinidine, сертиндол, терфенадин); the HMG-CoA reductase inhibitors which are metabolized CYP3A4 isoenzyme (ловастатин, симвастатин); concomitant oral administration of a triazolam and midazolam, ergot alkaloids (dihydroergotamine, ergometrine, ergotamine, methylergotamine), nisoldipina, eletriptana; pregnancy, lactation period.

Overdose:

Data are absent. At accidental overdose it is necessary to apply the supporting measures. Within the first hour to carry out a gastric lavage and if it is necessary, to appoint absorbent carbon. Itrakonazol is not brought at a hemodialysis. Any specific antidote does not exist.

Storage conditions:

List B. In the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 100 mg. On 1, 3, 4, 5, 6 or 7 capsules in a blister strip packaging. On 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction in a pack from a cardboard.