Orungamin

General characteristics. Structure:

Active agent: итраконазол 100 mg,

Excipients: a gipromelloza (a gidroksipropilmetiltsellyuloz of E-5), butylmethacrylate, dimethylaminoethylmethacrylate and methylmethacrylate copolymer [1:2:1] (eudragit E-100), sucrose (sugar)).

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 in the relation:
■ 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 against action of an itrakonazol: Page of glabrata, S. of krusei, S. of 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 system mycoses), in 6-9 months — at onychomycoses (in process of change of nails).

Pharmacokinetics. At oral administration the maximum bioavailability of an itrakonazol is noted at reception of capsules right after food. The maximum concentration in plasma is reached within 3-3,5 hours after intake and makes 28,34 ng/ml. At long reception equilibrium concentration is reached within 1-2 weeks. Itrakonazol for 99,8% contacts proteins of plasma. Concentration of an itrakonazol in blood makes 60% of concentration in 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 2-3 times exceeded the corresponding concentration in plasma. Therapeutic concentration in tissues of a vagina remain within 2 days after the termination 3-day a 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 in a liver with formation of active metabolites, including a gidroksiitrakonazola. Is inhibitor of isoenzymes CYP3A4, CYP3A5 and CYP3A7.
Removal from plasma — two-phase: kidneys during 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 — 1-1.5 days. Is not removed when carrying out dialysis.

Indications to use:

 Damage of skin and mucous membranes:
— dermatomycoses;
— vulvovaginal candidiasis;
— multi-colored deprive,
— candidiasis of a mucous membrane of an oral cavity;
— keratomycosis;
— deep visceral candidiases.

• the onychomycoses caused by dermatophytes and/or yeast and mold mushrooms:
• system mycoses:

— system aspergillosis and candidiasis;
— a cryptococcosis (including cryptococcal meningitis): at patients with an immunodeficiency and at all patients with a cryptococcosis of the central nervous system итраконазол it has to be appointed only in cases if drugs of the first line of treatment are not applicable in this case or are not effective;
— histoplasmosis;
— sporotrichosis;
— paracoccidioidosis;
— zymonematosis;
— the other seldom found system mycoses.

Route of administration and doses:

Features of use:

• Prevention of reinfection requires simultaneous treatment of sexual partners and respect for personal hygiene. During treatment it is recommended to abstain from sexual contacts. At preservation of symptoms of an infection after completion of treatment, it is necessary to conduct a repeated microbiological research for the purpose of confirmation of the diagnosis.
• Efficiency of an itrakonazol for treatment of fungal infections at a heavy neutropenia is unknown therefore in such cases drug has to be used only at inefficiency of the 1st line of therapy.
• At emergence of risk factors of chronic heart failure (coronary heart disease, damage of heart valves, a serious illness of lungs, including a chronic obstructive pulmonary disease, the states which are followed by an edematous syndrome) during treatment itrakonazoly therapy should be cancelled.
• At reception of an itrakonazol at some patients passing and constant deafness was noted.
• 1 capsule of an orungamin contains 4 grain units (GU).

IMPACT ON ABILITY TO DRIVE THE CAR AND TO WORK WITH THE EQUIPMENT
Does not render impact on ability to drive the car and to work with the equipment.

Side effects:

- From bodies of a hemopoiesis: leukopenia, neutropenia, thrombocytopenia.
- Allergic reactions: serum disease, Quincke's disease, anaphylactic and anaphylactoid reactions, hypersensitivity.
- From integuments: toxic epidermal necrolysis, Stephens-Johnson's syndrome, mnogoformny erythema, exfoliative dermatitis, leykoklastichesky vasculitis, alopecia, photosensitization, small tortoiseshell, rash, itch.
- From a metabolism: gipertriglitseridemiya, hypopotassemia.
- From a nervous system: peripheral neuropathy, paresthesia, hypesthesia, dizziness.
- From organs of sight and hearing: a vision disorder, including a vagueness and a diplopia, a sonitus, passing
or constant deafness.
- From cardiovascular system: congestive heart failure.
- From respiratory system: fluid lungs.
- From the alimentary system: abdominal pain, vomiting, nausea, diarrhea, disturbance of flavoring perception, increase in activity of "hepatic" enzymes; dyspepsia, lock, hepatitis, hyperbilirubinemia; hepatotoxic, acute liver failure.
- From a musculoskeletal system: mialgiya, arthralgia.
- From urinogenital system: pollakiuria, urine incontience, disturbance of a menstrual cycle, erectile dysfunction.
- Other: hypostases.

Interaction with other medicines:

The medicines exerting impact on absorption of an itrakonazol.
The medicines reducing acidity of a gastric juice break absorption of an itrakonazol that is connected with solubility of covers of capsules.
The medicines exerting impact on metabolism of an itrakonazol. Itrakonazol is generally metabolized with participation of an isoenzyme of CYP3A4. At simultaneous use with rifampicin, rifabutiny, Phenytoinum, the being powerful inductors of an isoenzyme CYP3A4, 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 liver enzymes is not recommended.
Powerful inhibitors of an isoenzyme CYP3A4, such as ритонавир, индинавир, кларитромицин and erythromycin, can increase bioavailability of an itrakonazol.
Influence of an itrakonazol on metabolism of other medicines:
Itrakonazol can inhibit metabolism of the drugs which are substrates of isoenzymes CYP3A. Strengthening or prolongation of their action including side effects can be result of it. At use of the accompanying drugs it is necessary to study information concerning their metabolism. 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 should be taken into consideration at assessment of the inhibiting effect of an itrakonazol on metabolism of at the same time appointed drugs.
Medicines which to appoint along with itrakonazoly it is not recommended:
• Terfenadin, астемизол, bepridit, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, сертиндол, левацетилметадол, HMG-CoA reductase inhibitors, such as симвастатин and ловастатин.
• Midazolam for intake and to triazoles.
• Drugs of alkaloids of an ergot such as dihydroergotamine, ergometrine, ergotamine and methylergometrine.
• Nisoldipin
• Blockers of "slow" calcium channels can render a negative inotropic effect which amplifies at a concomitant use with itrakonazoly. At a concomitant use of an itrakonazol and blockers of "medical-foam" calcium channels it is necessary to be careful as metabolism of blockers of "slow" calcium channels can be reduced.
Drugs at which co-administration it is recommended to watch their concentration in plasma, action, side effects. If necessary the dose of these drugs should be reduced.
• indirect anticoagulants;
• HIV protease inhibitors (ритонавир, индинавир, саквинавир);
• some antineoplastic drugs (alkaloids of a periwinkle pink, including Vincristinum and vinblastine; бусульфан, dotsetakset, триметрексат);
• metaboliziruyemy CYP3A4 isoenzyme blockers of "slow" calcium channels (verapamil and derivatives of dihydropyridine);
• some immunodepressive means (cyclosporine, такролимус, сиролимус);
• some metaboliziruyemy CYP3A4 isoenzyme reductase GMG-KOA inhibitors (аторвастатин);
• some glucocorticosteroids (будесонид, dexamethasone, флутиказон and Methylprednisolonum); •. digoxin (because of R-glycoprotein inhibition);
• other drugs: carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, midazolam for intravenous administration, рифабутин, эбастин, ребоксетин, цилостазол, Disopyramidum, галофантрин, репаглинид, fentanyl.
Interaction between itrakonazoly, a zidovudine and fluvastatiny is not revealed. Influence of an itrakonazol on metabolism of ethinylestradiol and Norethisteronum was not noted. Influence on binding of proteins.
The researches in vitro showed lack of interaction between itrakonazoly and such medicines as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum and сульфамеразин at linkng with proteins of plasma.

Contraindications:

1. Hypersensitivity to an itrakonazol or excipients.
2. Chronic heart failure, including in the anamnesis (except for therapy of zhizneugrozhayushchy states). 3. Concomitant use of the following medicines:
• drugs, metaboliziruyemy an isoenzyme of CYP3A4 which can extend QT an interval (астемизол, bepridit, цизаприд, дофетилид, левацетилметадол, мизоластин, Pimozidum, quinidine, сертиндол, терфенадин