Итразол®

General characteristics. Structure:

Active ingredient: 100 mg of an itrakonazol in microgranules (pellets).

Excipients: sucrose, starch, gidroksipropilmetiltsellyuloza, half-oxameasures.

Synthetic antifungal broad-spectrum agent.

Pharmacological properties:

Pharmacodynamics. Itrakonazol — the synthetic antifungal broad-spectrum agent derivative of triazole. Inhibits synthesis of ergosterol of a cellular membrane of mushrooms that causes antifungal effect of drug. Itrakonazol is active concerning the infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epydermophyton floccosum), drozhzhepodobny mushrooms and yeast (Cryptococcus neoformans, Pityrosporum spp., Candida spp., including C.albicans, C.glabrata and C.krusei), Aspergillus spp., Histoplasma spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporthrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, and also other barmy and mold mushrooms.

Pharmacokinetics. At oral administration the maximum bioavailability of an itrakonazol is noted at reception of capsules at once after dense food. The maximum concentration in plasma is reached within 3-4 hours after intake. Removal from plasma is two-phase with a final elimination half-life from 1 to 1,5 days. At long reception equilibrium concentration is reached within 1-2 weeks. Equilibrium concentration of an itrakonazol in plasma in 3-4 hours after administration of drug makes 0,4 mkg/ml (100 mg at reception once a day), 1,1 mkg/ml (200 mg at reception once a day) and 2,0 mkg/ml (200 mg at reception two times a day). Itrakonazol for 99,8% contacts proteins of plasma. Accumulation of drug in keratinaceous fabrics, especially in skin, approximately by 4 times exceeds accumulation in plasma, and the speed of its removal depends on regeneration of epidermis.

Unlike concentration in plasma which do not give in to detection in 7 days after the therapy termination therapeutic concentration in skin remain within 2-4 weeks after the termination of a 4-week course of treatment. Itrakonazol is found in a keratin of nails in one week after an initiation of treatment and remains, at least within 6 months after end of a 3-month course of therapy. Itrakonazol is defined also in skin fat and to a lesser extent in sweat.

Itrakonazol is well distributed in fabrics which are subject to fungal infections. Concentration in lungs, kidneys, a liver, bones, a stomach, a spleen and muscles by two-three times exceeded the corresponding concentration in plasma. Therapeutic concentration in tissues of a vagina remain within 2 days after the termination of a 3-day course of treatment in a dose of 200 mg a day, and 3 days after the termination of a one-day course of treatment in a dose of 200 mg twice a day.

Itrakonazol is metabolized by a liver with formation of a large number of metabolites. One of such metabolites is hydroxy-itrakonazol which possesses comparable with itrakonazoly antifungal action of in vitro.protivogribkovye of concentration of drug, determined by a microbiological method, approximately by 3 times exceeded the concentration measured by means of VZhH (a high-liquid hromatogramma). Removal with a stake makes from 3 to 18% of a dose. Removal by kidneys makes less than 0,03% of a dose. About 35% of a dose are allocated in the form of metabolites with urine within 1 week.

Indications to use:

ИТРАЗОЛ® in capsules it is shown for treatment of the following diseases:
- dermatomycoses;
- fungal keratitis;
- the onychomycoses caused by dermatophytes and/or yeast and mold mushrooms;
- system mycoses: a system aspergillosis and candidiasis, a cryptococcosis (including cryptococcal meningitis), histoplasmosis, a sporotrichosis, a paracoccidioidomycosis, a zymonematosis and other, system or tropical mycoses.
- candidiases with damage of skin or mucous, including vulvovaginal candidiasis;
- deep visceral candidiases;
- chromophytosis.

Route of administration and doses:

For optimum absorption of drug it is necessary to accept ИТРАЗОЛ® in capsules right after food. It is necessary to swallow of capsules entirely.

Indication	Dose	Duration
Vulvovaginal candidiasis	200 mg 2 times a day or 200 mg of 1 times a day	1 day 3 days
Chromophytosis	200 mg of 1 times a day	7 days
Dermatomycosis of smooth skin	200 mg of 1 times a day or 100 mg of 1 times a day	7 days 15 days
Defeats of high-keratinized areas of an integument, such as hands and feet	200 mg 2 times a day or 100 mg of 1 times a day	7 days 30 days
Candidiasis of a mucous membrane of an oral cavity	100 mg of 1 times a day	15 days
Fungal keratitis	200 mg of 1 times a day	21 days Correction of duration is possible treatments taking into account positive loudspeakers of a clinical picture

Defeats of the high-keratinized areas of an integument, such as hands and feet, demand additional treatment within 15 days on 100 mg a day.

Bioavailability of an itrakonazol at oral administration can be reduced at some patients with the broken immunity, for example, at patients with a neutropenia, patients with AIDS or with transplanted organs. Therefore, increase in a dose can be required twice.

Onychomycosis. Pulse therapy (see the table). One course pulse therapy consists in daily reception on 2 ITRAZOL® capsules two times a day (on 200 mg two times a day) within one week. For treatment of fungal infections of nail plates of brushes two courses are recommended. For treatment of fungal infections of nail plates of feet three courses are recommended (see the table). The interval between courses during which it is not necessary to accept drug makes 3 weeks. Clinical results will become obvious after the end of treatment, in process of growth of nails.

Localization of onychomycoses	The 1st week.	The 2nd week.	The 3rd week.	The 4th week.	The 5th week.	The 6th week.	The 7th week.	The 8th week.	The 9th week.
Defeat of nail plates of brushes	The 1st course	Weeks, free from reception Итразола®			The 2nd course
Defeat of nail plates of feet with defeat or without defeat of nail plates of brushes	The 1st course	Weeks, free from reception Итразола®			The 2nd course	Weeks, free from reception Итразола®			The 3rd course

Continuous treatment: On two capsules a day (on 200 mg once a day) within 3 months.

Removal ИТРАЗОЛ® 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.

• System mycoses (the recommended dosages vary in dependence that a type of an infection)

Indication	Dose	Average duration	Notes
Aspergillosis	200 mg 1 time a day	2-5 months	In case of the invasive or disseminated disease about 200 mg 2 times a day are recommended to increase a dose
Candidiasis	100-200 mg 1 time a day	from 3 weeks to 7 months	In case of the invasive or disseminated disease about 200 mg 2 times a day are recommended to increase a dose
Cryptococcosis (except meningitis)	200 mg 1 time a day	from 2 months to 1 year
Cryptococcal meningitis	200 mg two times a day	from 2 months to 1 year	Maintenance therapy of 200 mg of 1 times a day
Histoplasmosis	from 200 mg of 1 times a day to 200 mg two times a day	8 months
Zymonematosis	from 100 mg of 1 times a day to 200 mg two times a day	6 months
Sporotrichosis	100 mg of 1 times a day	3 months
Paracoccidioidomycosis	100 mg of 1 times a day	6 months
Chromomycosis	100-200 mg of 1 times a day	6 months

Features of use:

- At the research of an intravenous dosage form of drug of Itrazolv conducted on healthy volunteers the passing bessimtomny reduction of fraction of emission of a left ventricle normalized before the following infusion of drug was noted. The clinical importance of the obtained data for peroral dosage forms is unknown.

- It is revealed what итраконазол possesses a negative inotropic effect. It was reported about the cases of development of heart failure connected with reception of Itrazolav. ИтразолВ 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 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 heart failure. Treatment has to is carried out with care, at the same time it is necessary to watch the patient regarding identification of symptoms of congestive heart failure. At their emergence reception of Itrazolav needs to be stopped.

- Blockers of calcium channels can render a negative inotropic effect which can strengthen similar effect of an itrakonazol; итраконазол can reduce metabolism of blockers of calcium channels. At a concomitant use of an itrakonazol and blockers of calcium channels it is necessary to be careful.

- At the lowered acidity of a stomach: absorption of an itrakonazol 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 Itrazol. To patients with an achlorhydria or the applying H2 - gistaminoblokator or inhibitors of a protonew pomp, it is recommended to accept the IRAZOL® capsules with acid drinks.

- Seldom or never at use ИТРАЗОЛ® crushing toxic damage of a liver, including cases of an acute liver failure with a lethal outcome developed. In most cases it happened to patients who already had liver diseases, for the patients who were receiving therapy according to system indications, having other serious medical states and also for 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 case of such symptoms it is necessary to stop immediately therapy and to conduct a research of function of a liver. To patients with a superactivity of "hepatic" 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 ИТРАЗОЛ® unless the expected advantage justifies risk of damage of a liver. In these cases it is necessary to control activity of "hepatic" enzymes during treatment.

- Abnormal liver functions: Itrakonazol is metabolized preferential in a liver. The elimination half-life of an itrakonazol at patients with cirrhosis is a little increased. Bioavailability of drug at oral administration is a little reduced at patients with cirrhosis. In this case, perhaps, dose adjustment will be necessary. Lasting reception more than one month control of function of a liver is necessary.

- Renal failures: at patients with a renal failure bioavailability of an itrakonazol can be reduced. In this case, perhaps, dose adjustment will be necessary.
- Treatment should be stopped when developing neuropathy which can be connected with reception of capsules of Itrazolav.

- There are no data of cross hypersensitivity to an itrakonazol and other azolovy antifungal drugs. ИтразолВ in capsules patients should appoint with care with hypersensitivity to other azoles.

- At patients with the broken immunity (AIDS, after organ transplantation, a neutropenia) increase in a dose can be required.
 
Impact on ability to drive the car and to work with the equipment. It was not observed.

Use in pediatrics. As capsules children have not enough clinical data on use of an itrakonazol, it is recommended to use итраконазол only if the possible advantage surpasses potential risk.

Use during pregnancy and a lactation. On the basis of results of preclinical trials and because researches on use of an itrakonazol for pregnant women were not conducted, итраконазол pregnant women should appoint only at life-threatening system mycoses when the potential advantage for women justifies possible risk for a fruit.

As a small amount of an itrakonazol is allocated with maternal milk, the expected advantage of reception of an itrakonazol needs to be compared with risk for the child when breastfeeding. In case of doubts it is not necessary to nurse.

Side effects:

Reactions from digestive tract, such as were the most often noted side reactions in connection with use of an itrakonazol: dyspepsia, nausea, abdominal pain and lock. Besides, were noted: anorexia headache, fatigue, reversible increase in activity of "hepatic" enzymes, cholestatic jaundice, hepatitis, disturbance of a menstrual cycle, dizziness and allergic reactions (such as itch, rash, urticaria and Quincke's disease), peripheral neuropathy, Stephens-Johnson's syndrome, an alopecia, a hypopotassemia, hypostases, congestive heart failure and a fluid lungs, coloring of urine in dark color, a giperkreatininemiya.

Seldom or never at use ИТРАЗОЛ® crushing toxic damage of a liver, including cases of an acute liver failure with a lethal outcome developed.

Interaction with other medicines:

1. The medicines exerting impact on metabolism of an itrakonazol.
Interaction of an itrakonazol with rifampicin, rifabutiny and Phenytoinum was studied. Simultaneous use of an itrakonazol with these drugs which are potential inductors of liver enzymes is not recommended. Interaction researches with other inductors of liver enzymes, such as carbamazepine, phenobarbital and isoniazid, were not conducted, however, similar results it is possible to assume.

As итраконазол it is generally metabolized by CYP 3A4 enzyme, potential inhibitors of this enzyme can increase bioavailability of an itrakonazol. Can be examples ритонавир, индинавир, кларитромицин and erythromycin.

2. Influence of an itrakonazol on metabolism of other medicines. Itrakonazol can inhibit metabolism of the drugs split by CYP3A4 enzyme. Strengthening or prolongation of their action including side effects can be result of it. After the treatment termination levels of an itrakonazol in plasma decrease gradually depending on a dose and duration of treatment (see the section Pharmacokinetics). Examples of such drugs are:
Drugs which it is impossible to appoint along with itrakonazoly:
• Terfenadin, астемизол, мизоластин, цизаприд, to triazoles and midazolam, дофетилид, quinidine, Pimozidum, inhibitors of GMG-KOA reductase such, as симвастатин and ловастатин.
• Blockers of calcium channels can render a negative inotropic effect which can strengthen the same effect shown itrakonazoly. At a concomitant use of an itrakonazol and blockers of calcium channels it is necessary to be careful as metabolism of blockers of calcium channels can be reduced.

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.
• Peroral anticoagulants;
• HIV protease inhibitors, such, as ритонавир, индинавир, саквинавир;
• Some antineoplastic drugs, such as alkaloids of the Periwinkle pink, бусульфан, dotsetakset, триметрексат;
• The blockers of calcium channels split by CYP3A4 enzyme, such as dihydropyridine and verapamil;
• Some immunosuppressive means: cyclosporine, такролимус, сиролимус;
• Dugy drugs: digoxin, carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, рифабутин, Methylprednisolonum, эбастин, ребоксетин.
Interaction between itrakonazoly and a zidovudine and fluvastatiny is not revealed.
Influence of an itrakonazol on metabolism of ethinylestradiol and Norethisteronum was not noted.

3. Influence on binding of proteins. The researches in vitro showed lack of the competition between itrakonazoly and such drugs as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum and Sulfamethazinum for communication with proteins of plasma.

Contraindications:

- ИТРАЗОЛ® in capsules it is contraindicated to patients with individual hypersensitivity to drug or its components.
- Pregnant women Itrazol should appoint only if the expected advantage for the woman exceeds potential risk for a fruit. The women of childbearing age accepting Itrazol need to use adequate methods of contraception throughout all course of treatment up to approach of the first periods after its end.
- With care: children's age, heavy heart failure, liver diseases (including followed by a liver failure).
- Terfenadin, астемизол, мизоластин, цизаприд, дофетилид, the quinidine, Pimozidum which are metabolized with CYP3A4 enzyme participation inhibitors of GMG-KOA reductase such as симвастатин and ловастатин, triazoles and midazolam cannot accept along with Itrazol. (see also section "Interactions with Other Medicines").

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. At a temperature not over 25 ºС in dry, protected from light and the place, unavailable to children. Period of validity: 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Capsules on 100 mg. On 6 or 7 capsules in a blister strip packaging or on 6 or 14 capsules in bank of polymeric. 1 blister strip packaging on 6 capsules or 2 blister strip packagings on 7 capsules, or one bank together with the application instruction in a pack from a cardboard.