Orunit

General characteristics. Structure:

Active ingredient: 464 mg of pellets of an itrakonazol (the specified quantity is given much in relation to 100 mg) in 1 capsule.

Excipients: to a gipromelloza-a 5, sucrose, methylparahydroxysodium benzoate, пропилпарагидроксибензоат sodium, a sugar krupka [sucrose, starch syrup], an eudragit-a 100 [weed (butilmetakrilat-so-(2 dimethylaminoethyl) methacrylate-with-methylmethacrylate) 1:2:1];

Gelatinous solid capsules (gelatin, dye azoruby, titanium dioxide, indigo carmine).

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 zheludochno intestinal path (ZIP) 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 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 (T 1/2) - 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, capsules are swallowed entirely, right after food.

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 acquired immunodeficiency syndrome (AIDS) or with transplanted organs. Therefore, double increase in a dose can be required.

Removal of an itrakonazol 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:

Use at pregnancy and during breastfeeding: drug is contraindicated to use throughout pregnancy and during breastfeeding.

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

It is revealed what интраконазол possesses a negative inotropic effect. It was reported about cases of HSN connected with reception of an intrakonazol. Intrakonazol patients should not accept with HSN, 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 dosing mode, individual risk factors of emergence and aggravation of HSN into account. Risk factors include existence of heart diseases, such as an ischemic heart disease or defeats of valves; serious diseases of lungs, such as obstructive defeats; the renal failure or other diseases which are followed by hypostases. Treatment has to be carried out with care, at the same time it is necessary to inform the patient on signs and symptoms of congestive heart failure, to monitorirovat it in dynamics. At emergence or aggravation of symptoms of HSN treatment intrakonazoly needs to be stopped.

At the lowered acidity of a stomach absorption of an intrakonazol from capsules is broken. Reception of antiacid drugs is recommended not earlier than in 2 hours after reception of capsules of an intrakonazol. To patients with an achlorhydria or applying blockers of H2-histamine receptors and inhibitors of a proton pomp, it is recommended to accept capsules of an intrakonazol with the drinks containing Coca.

Seldom or never at use of an intrakonazol 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 and also at the patients receiving other HP possessing a hepatotoxic action. Several such cases arose in the first month of therapy, some – in the first week of treatment. Due to these it is regularly recommended to control function of a liver at the patients receiving therapy intrakonazoly. Patients should be warned about need to contact immediately the doctor in case of developing of anorexia, nausea, vomiting, weakness, an abdominal pain, urine darkening – the symptoms assuming developing of hepatitis. In case of such symptoms it is necessary to stop immediately therapy and to conduct a research of functions of a liver. Patients with the increased concentration of "hepatic" enzymes or an active disease of a liver, and also at reception of potentially hepatotoxic HP, should not appoint treatment intrakonazoly unless the expected advantage justifies risk of damage of a liver. As интраконазол it is metabolized preferential in a liver, it is recommended to exercise control of concentration of an intrakonazol in plasma and if necessary to adjust a drug dose.

As at patients with a renal failure of T1/2 of an intrakonazol it is a little increased, it is also recommended to exercise control of concentration of an intrakonazol in plasma and if necessary to adjust a drug dose.

Bioavailability of an intrakonazol can be reduced at some patients with the broken immunity, for example, at patients with a neutropenia, AIDS or undergone an operation on organ transplantation.

With the system fungal infections posing a threat for life интраконазол orally to start treatment it is not recommended to patients.

Children should not appoint capsules of an intrakonazol, except for cases when the expected advantage exceeds possible risk.

Treatment intrakonazoly should be stopped when developing peripheral neuropathy which can be connected with reception of capsules of an intrakonazol.

Influence on ability to manage the vehicle and other difficult mechanisms. Intrakonazol can cause dizziness and other side effects which can affect ability to drive the car and other equipment demanding is raised attention during the work.

Side effects:

Frequency of the side effects developing at reception of a karvedilol 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%, including separate messages.

From a GIT: often – an abdominal pain, vomiting, nausea, diarrhea, disturbance of flavoring perception, reversible increase in activity of "hepatic" enzymes; infrequently – dyspepsia, a lock, hepatitis, a hyperbilirubinemia; very seldom – a hepatotoxic, an acute liver failure.

From a nervous system: often – a headache; infrequently – peripheral neuropathy, dizziness; very seldom – paresthesia, a hypesthesia.

From immune system: seldom - anaphylactic and anaphylactoid reactions.

From integuments: often – rash; infrequently – an itch; very seldom – a toxic epidermal necrolysis, a multiformny exudative erythema (Stephens-Johnson's syndrome), exfoliative dermatitis, a leykoklastichesky vasculitis, a small tortoiseshell, an alopecia, a photosensitization.

From bodies of a hemopoiesis: infrequently – a leukopenia, a neutropenia, thrombocytopenia.

From a metabolism: infrequently – a hypopotassemia; very seldom – a gipertriglitseridemiya.

From sense bodys: infrequently – a vision disorder, including a vagueness and a diplopia; very seldom – a sonitus, passing or constant deafness.

From cardiovascular system: very seldom – congestive heart failure.

From respiratory system: very seldom – a fluid lungs.

From a musculoskeletal system: very seldom – a mialgiya, an arthralgia.

From urinogenital system: very seldom – a pollakiuria, an urine incontience, menstrual disturbances, erectile dysfunction.

Others: infrequently – hypostases.

Interaction with other medicines:

The Medicines (M) reducing acidity of a gastric juice break absorption of an itrakonazol that is connected with solubility of covers of capsules.

CYP3A4 isoenzyme inductors (including rifampicin, рифабутин, Phenytoinum) reduce bioavailability of an itrakonazol and gidroksiintrakonazol that leads to essential reduction of efficiency of drug. Therefore simultaneous use of an intrakonazol with these drugs which are potential inductors of microsomal enzymes of a liver is not recommended. Similar results can be assumed at combined use of an intrakonazol with other inductors of microsomal enzymes of a liver (carbamazepine, phenobarbital, an isoniazid) though researches of their interaction were not conducted.

CYP3A4 isoenzyme inhibitors (including ритонавир, индинавир, кларитромицин, erythromycin) can increase bioavailability of an intrakonazol.

Itrakonazol prolongs and strengthens action of HP (including collateral), metabolized CYP3A4 isoenzyme.

Extra care should be observed at a concomitant use with intrakonazoly the following HP:

· indirect anticoagulants;

· HIV protease inhibitors (ритонавир, индинавир, саквинавир);

· some antineoplastic HP (бусульфан, dotsetakset, триметрексат, periwinkle alkaloids);

· blockers of "slow calcium channels", metabolized CYP3A4 isoenzyme (dihydropyridines, verapamil);

· some immunodepressants (cyclosporine, такролимус, сиролимус);

· metaboliziruyemy isoenzyme of CYP3A4 of inhibitors of GMG-KOA reductase (аторвастатин);

· some glucocorticosteroids (будесонид, dexamethasone, флутиказон, Methylprednisolonum);

· other HP (digoxin (at the expense of P-glycoprotein inhibition), цилостазол, Disopyramidum, carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, midazolam (in/in), рифабутин, эбастин, репаглинид, fentanyl, галофантрин, ребоксетин, loperamide, элетриптан).

At joint appointment with intrakonazoly above-mentioned HP it is necessary to watch their concentration in plasma, action, side effects.

Drugs which it is impossible to appoint along with intrakonazoly:

· терфенадин, астемизол, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, левацетилметадол, сертиндол – combined use of data of HP with intrakonazoly 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;

· 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 "slow 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 "slow calcium channels" can render a negative inotropic effect which amplifies at a concomitant use and intrakonazoly.

Interaction between intrakonazoly and a zidovudine and fluvastatiny is not revealed.

Influence of an intrakonazol on metabolism of ethinylestradiol and Norethisteronum was not noted.

Contraindications:

Hypersensitivity, the chronic heart failure (CHF), 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, the lactation period, children's age up to three years (for this dosage form).

With care: Renal or liver failure, peripheral neuropathy, risk factors: HSN (the coronary heart disease (CHD), damage of heart valves, a serious illness of lungs, including a chronic obstructive pulmonary disease, the states which are followed by an edematous syndrome), a hearing disorder, a concomitant use of blockers of slow calcium channels, children's and advanced age.

Overdose:

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

Storage conditions:

In the dry, protected from light place at a temperature not over 25 ºС. To store in the place, unavailable to children. A period of validity - 3 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules on 100 mg. On 5, 6 or 15 capsules in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2 or 3 blister strip packagings on 5, 6 capsules or 1 blister strip packaging on 15 capsules together with the application instruction place in a pack from a cardboard.