Orungal

General characteristics. Structure:

Active agent: итраконазол – 100 mg.

Excipients: sucrose – 192,0 mg, a gipromelloza – 150,0 mg, a macrogoal of 20000 - 18,0 mg. Cover of capsules: gelatin – 93,2 mg, titanium dye dioxide (E171) – 2,8 mg, dye indigo carmine (E132) – enough, dye an azoruby (E122) – enough.

Description. The solid gelatin capsules No. 0 consisting of the transparent case of pink color and an opaque lid of blue color. Contents of capsules – pellets of cream color.

Pharmacological properties:

Pharmacodynamics.

Орунгал® – the synthetic antifungal broad-spectrum agent containing итраконазол derivative triazole. The mechanism of action of an itrakonazol consists in ergosterol biosynthesis inhibition – the main component of a cellular membrane of the mushroom participating in maintenance of structural integrity of a membrane. Disturbance of synthesis of ergosterol leads to change of permeability of a membrane and a lysis of a cell, as causes antifungal effect of drug.

Itrakonazol is active concerning the infections caused by mushrooms:

- dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum);

- drozhzhepodobny mushrooms (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis, C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidiodes immitis, Pseudallescheria boydii; Penicillium marneffei and many others.

Candida krusei, Candida glabrata and Candida tropicalis are the types of Candida, least sensitive to action of an itrakonazol. The main types of mushrooms which development is not suppressed itrakonazoly are Zygomyces (Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

Azoles resistance develops slowly and often is result of several genetic mutations. The described mechanisms of development of stability include a hyper expression of a gene of ERG11 coding enzyme 14α-to a demetilaz which is the main target of effect of azoles, and the dot mutations of ERG11 leading to reduction of linkng of enzymes with azoles and/or to activation of transport systems that leads to increase in removal of azoles. Cross stability of Candida spp was observed. to drugs of group of azoles though stability to one drug of this group optional means existence of stability to other drugs of group of azoles. It was reported about strains of Aspergillus fumigates steady against an itrakonazol.

Pharmacokinetics.

Owing to nonlinear pharmacokinetics итраконазол collects in a blood plasma at multiple dose. Equilibrium concentration of an itrakonazol is, as a rule, reached within about 15 days, at the same time values of the maximum concentration (Cmax) of an itrakonazol and AUC (the area under a curve "concentration time") at multiple dose are 4 - 7 times higher, than at a single dose. The maximum equilibrium concentration of an itrakonazol in plasma (Cssmax) makes about 2 mkg/ml at purpose of 200 mg of an itrakonazol once a day. The final elimination half-life usually makes 16 – 28 hours at a single dose and 34 – 42 hours at multiple dose. Concentration of an itrakonazol in a blood plasma снижаетсядо almost not defined value within 7 – 14 days, after the termination of therapy depending on the appointed dose and duration of treatment. The clearance of an itrakonazol decreases at higher doses in connection with saturation of ways of its metabolization in a liver.

Absorption.

Itrakonazol is quickly absorbed after intake. The maximum concentration of not changed itrakonazol in plasma are reached within 2-5 hours after oral administration. Absolute bioavailability of an itrakonazol after oral administration makes about 55%. At oral administration the maximum bioavailability of an itrakonazol is noted at reception of capsules right after food.

Absorption of an itrakonazol in capsules is reduced at the patients with the lowered acidity of a gastric juice, for example, against the background of administration of drugs suppressing secretion of hydrochloric acid in a stomach (such as antagonists of H2 - histamine receptors, inhibitors of a proton pomp), or at patients with an achlorhydria against the background of various diseases. Absorption of an itrakonazol on an empty stomach at such patients increases at administration of drug of Orungal®, the capsule along with acid drinks (such as not dietary Coca). At administration of drug of Orungal®, the capsule, in a dose of 200 mg once on an empty stomach together with not dietary Coca after preliminary reception of the antagonist of H2 - histamine receptors of ranitidine absorption of an itrakonazol was comparable to absorption of the drug Orungal®, the capsule at reception only of this drug.

Exposure of an itrakonazol is lower at reception of an itrakonazol in the form of capsules in comparison with exposure of an itrakonazol at reception of the same dose in the form of solution for intake.

Distribution.

Itrakonazol for 99,8% contacts proteins of plasma, generally albumine (гидроксиитраконазол contacts albumine for 99,6%). Affinity to lipids is also noted. In an untied look in plasma there are only 0,2% of an itrakonazol. The seeming distribution volume> 700 l that demonstrates its considerable distribution in fabrics. Concentration in lungs, kidneys, bones, a stomach, a spleen and muscles, are 2-3 times higher, than the corresponding concentration in plasma, at the same time concentration of drug in the fabrics containing a keratin, especially in skin, approximately by 4 times exceeds concentration in plasma. Concentration in cerebrospinal fluid is much lower, than in a blood plasma, nevertheless, efficiency of an itrakonazol against causative agents of the infections which are present at cerebrospinal liquid was shown.

Metabolism.  

As it was shown in the researches in vitro, CYP3A4 is the main isoenzyme participating in metabolism of an itrakonazol. Itrakonazol is exposed to active metabolism in a liver with formation of a set of metabolites. The main metabolite is гидроксиитраконазол which in vitro has the antifungal activity comparable with itrakonazoly. Concentration of a gidroksiitrakonazol in plasma exceed concentration of an itrakonazol approximately twice.

Excretion.

Itrakonazol is brought preferential in the form of inactive metabolites with urine (35%) and a stake (54%) within one week after reception of solution for intake. Renal excretion of an itrakonazol and its active metabolite of a gidroksiitrakonazol makes less than 1% of the dose of drug entered intravenously. On the basis of results of studying of pharmacokinetics of 14C-marked drug after oral administration removal of not changed itrakonazol with a stake varies from 3% to 18% of the accepted dose. As redistribution of an itrakonazol from the fabrics containing a keratin is insignificant, removal of an itrakonazol of their these fabrics is connected with regeneration of epidermis. Unlike a blood plasma, concentration of an itrakonazol in skin remains within from 2 to 4 weeks after the termination of 4 weeks treatment, and concentration in a nail keratin where итраконазол it can be found in 1 week after an initiation of treatment, remains, at least, within six months after the termination of a 3kh-month course of treatment.

Special categories of patients:

Abnormal liver function. Itrakonazol is preferential metabolized in a liver. During the research of pharmacokinetics compared pharmacokinetic indicators of patients to cirrhosis and healthy volunteers. At patients with cirrhosis at an odnokratnompriyema of 100 mg of an itrakonazol average maximum concentration of an itrakonazol to a vpriyema of 100 mg of an itrakonazol average maximum concentration of an itrakonazol in plasma (C max) was much lower (for 47%), than at healthy patients. The average elimination half-life at reception of a single dose was increased at patients with cirrhosis and made in this research of 37+17 hours in comparison with 16+5 hours for healthy volunteers. Average exposure of an itrakonazol (the area under a curve "concentration time" - AUC) was similar at patients with cirrhosis and at healthy volunteers. Data on prolonged use of an itrakonazol at patients with cirrhosis are absent (see the sections "Route of Administration and Doses" and "Special Instructions").

Renal failure. Data on oral administration of an itrakonazol for treatment of patients with renal failures are limited. At patients with uraemia at whom the average clearance of creatinine made 13 ml/min. x 1,73 sq.m system influence of an itrakonazol (AUC) was slightly lower in comparison with the main population. Considerable influence of the hemodialysis or long peritoneal dialysis which is carried out in out-patient conditions on indicators of pharmacokinetics of an itrakonazol is not revealed (T max, C max and AUC0-8ch).

After single intravenous administration of drug a final elimination half-life of an itrakonazol at patients with insignificant (decides in a research as clearance of creatinine of 50-79 ml/min.), an average (clearance of creatinine of 20 - 49 ml/min.) or the expressed renal failure (clearance of creatinine <20 ml/min.) similar on that at healthy people (range of average values of 42-49 hours in comparison with 48 hours at patients with renal failures and healthy volunteers, respectively). The general exposure of an itrakonazol, on the basis of AUC indicator assessment, was reduced at patients with the moderated and expressed renal failures approximately by 30% and 40%, respectively, in comparison with patients at whom function of kidneys is not broken.

Data on long use of an itrakonazol by patients with renal failures are not available. Carrying out dialysis does not influence an elimination half-life or clearance of an itrakonazol or gidroksiitrakonazol.

Children. Data on pharmacokinetics of an itrakonazol at patients of children's age are limited. Clinical trials of pharmacokinetics at children and teenagers aged from 5 months up to 17 years were carried out using an itrakonazol in capsules, solution for intake and solution for intravenous administration. Individual doses of drug in the form of capsules and solution for intake varied from 1,5 to 12,5 mg/kg/day at reception one or twice a day. At administration of drug in the same daily dose twice a day in comparison with reception once a day adult patients had a comparable maximum and minimum plasma concentration to that at reception of an itrakonazol once a day. Essential age distinctions of indicators of AUC of an itrakonazol and its general clearance were not registered; the insignificant interrelation between age of patients and values of volume of distribution of drug, C max and a final elimination half-life was in rare instances observed. The established clearance of an itrakonazol and its volume of distribution depend on the body weight of patients.

Indications to use:

- damage of skin and mucous membranes:

  − vulvovaginal candidiasis;

  − chromophytosis.

  − dermatomycoses;

  − candidiasis of a mucous membrane of an oral cavity;

  − fungal keratitis;

− the onychomycoses caused by dermatophytes and/or drozhzhepodobny 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 of Orungal® 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,

  − zymonematosis,

  − sporotrichosis,

  − paracoccidioidomycosis,

  − the other seldom found system or tropical mycoses.

Route of administration and doses:

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

Indication. Dose. 

Vulvovaginal candidiasis: 200 mg 2 times a day or 200 mg of 1 times a day. Treatment duration: 1 days or 3 days.

Chromophytosis: 200 mg of 1 times a day. Treatment duration: 7 days.

Dermatomycoses of smooth skin of 200 mg of 1 times a day or 100 mg of 1 times a day. Treatment duration: 7 days or 15 days.

Defeats of the high-keratinized areas of an integument, such as hands and feet of 200 mg of 2 times a day or 100 mg of 1 times a day. Treatment duration: 7 days or 30 days.

Candidiasis of a mucous membrane of an oral cavity of 100 mg of 1 times a day. Treatment duration: 15 days.

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, double increase in a dose can be required.

Fungal keratitis: 200 mg of 1 times a day. Treatment duration: 21 days Duration of treatment can be corrected depending on improvement of a clinical picture.

The onychomycoses caused by dermatophytes and/or drozhzhepodobny and mold mushrooms.

Onychomycoses: pulse therapy One course pulse therapy consists in daily reception on 2 capsules of the drug Orungal® 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. 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:

- Defeat of nail plates of fingers of feet with defeat or without defeat of nail plates of fingers of brushes the 1st course;

- Defeat of nail plates of brushes 1st course.

2 weeks 3 weeks 4 weeks the 5th week:

- Defeat of nail plates of fingers of feet with defeat or without defeat of nail plates of fingers of brushes the 2nd course. Weeks, free from administration of drug of Orungal®;

- Defeat of nail plates of brushes 2nd course. Weeks, free from administration of drug of Orungal®.

The 6th week the 7th week the 8th week the 9th week:

- Defeat of nail plates of fingers of feet with defeat or without defeat of nail plates of fingers of brushes the 3rd course. Weeks, free from administration of drug of Orungal®.

Onychomycoses – continuous treatment:

Defeat of nail plates of feet with defeat or without defeat of nail plates of brushes On 200 mg a day. Treatment duration: 3 months.

Removal of the drug Orungal® 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:

Indication. Dose. Average duration лечения*. Notes.

- Aspergillosis: 200 mg of 1 times a day. Average duration of treatment: 2-5 months. Notes: to increase a dose to 200 mg 2 times a day in case of the invasive or disseminated disease.

- Candidiasis: 100-200 mg of 1 times a day. Average duration of treatment: from 3 weeks to 7 months. Notes: to increase a dose to 200 mg 2 times a day in case of the invasive or disseminated disease.

- A cryptococcosis (except meningitis): 200 mg of 1 times a day. Average duration of treatment: from 2 months to 1 year. 

- Cryptococcal meningitis: 200 mg two times a day. Average duration of treatment: from 2 months to 1 year. Notes: a maintenance therapy – see the section "Special Instructions".

- Histoplasmosis: from 200 mg of 1 times a day to 200 mg two times a day. Average duration of treatment: 8 months.

- Zymonematosis: from 100 mg of 1 times days to 200 mg two times a day. Average duration of treatment: 6 esyaets.

- Sporotrichosis: 100 mg of 1 times a day. Average duration of treatment: 3 esyaets.

- Parakoktsidioido-mikoz: 100 mg of 1 times a day. Average duration of treatment: 6 months. Notes: data on efficiency of this dose for treatment of parakoktsidioido-mycosis at patients with AIDS are absent.

- Chromomycosis: 100-200 mg of 1 times a day. Average duration of treatment: 6 months. 

* - duration of treatment can be corrected depending on efficiency of treatment.

Special groups of patients.

Children. Data, about use of the drug Orungal®, capsules, for treatment of children are limited. Use of the drug Orungal®, the capsule, for treatment of children is not recommended, except for cases when the expected advantage of treatment surpasses potential risk.

Elderly patients. Data on use of the drug Orungal®, the capsule, for treatment of patients of advanced age are limited. It is recommended to use the drug Orungal®, capsules, for treatment of patients of this category, only if the expected advantage of treatment exceeds potential risks. At the choice of a dose of drug for treatment of elderly patients it is recommended to consider depression of function of a liver, the kidneys and heart meeting at advanced age more often and also existence of associated diseases or reception of other medicines.

Abnormal liver functions. Data on use of a peroral itrakonazol for treatment of patients with abnormal liver functions are limited. It is necessary to appoint drug of this category of patients with care.

Renal failures. Data on use of a peroral itrakonazol for treatment of patients with renal failures, are limited. At some patients having a renal failure, exposure of an itrakonazol can be reduced. It is necessary to appoint drug of this category of patients with care, change of a dose of medicine in certain cases can be required.

Features of use:

− Influence on action of the heart: in a research of a dosage form of the drug Orungal® for intravenous administration the passing asymptomatic 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. Itrakonazol possesses a negative inotropic effect. It was reported about the cases of chronic heart failure connected with administration of drug of Orungal®. At a daily dose of 400 mg of an itrakonazol more frequent developing of heart failure was observed; at smaller daily doses of such pattern it was not revealed. The risk of developing of chronic heart failure is presumably proportional to a daily dose. The drug Orungal® should not be accepted to patients with chronic heart failure or with existence of this symptom complex 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 into account such factors as gravity of indications, the mode of dosing and individual risk factors of developing of heart failure (coronary heart disease, defeats of valves, the obstructive pulmonary diseases, a renal failure and other diseases which are followed by hypostases). Such patients need to be informed on signs and symptoms of chronic heart failure and to monitor their emergence during a course of treatment. At emergence of similar signs administration of drug of Orungal® needs to be stopped. Life-threatening arrhythmias of heart and/or sudden death were noted at patients at simultaneous use of methadone.

− Medicinal interactions: the concomitant use of some medicines with itrakonazoly can lead to change in efficiency of an itrakonazol and/or at the same time used medicines, emergence of life-threatening side reactions and/or sudden death. Drugs which cannot be accepted along with itrakonazoly, not recommended for simultaneous use and/or recommended for simultaneous use with itrakonazoly with care, are listed in the section "Interaction with Other Medicines".

− Cross hypersensitivity: given concerning existence of cross hypersensitivity between itrakonazoly and other antifungal means with azolny structure (from group of azoles) are limited. With hypersensitivity to other azoles it is necessary to appoint with care итраконазол.

− Interchangeability: interchangeable use of the drugs Orungal®, capsules, and Orungal®, solution for intake is not recommended in view of the fact that exposure of an itrakonazol is higher when using than it in the form of solution for intake, than in the form of capsules, even at reception of identical doses of an itrakonazol.

− Reduced acidity of a gastric juice: at reduced acidity of a gastric juice absorption of an itrakonazol from capsules is broken. To patients with reduced acidity of a gastric juice owing to a disease (for example, at patients with an achlorhydria) or owing to reception of medicines (for example, the medicines suppressing gastric secretion), Orungal® in capsules along with acid drinks is recommended to accept (such as not dietary Coca). It is necessary to control antifungal activity of drug and to increase a dose of an itrakonazol if necessary.

– Influence on function of a liver: seldom or never at use of the drug Orungal® crushing toxic damage of a liver developed, including several cases of an acute liver failure with a lethal outcome. In most cases it happened to patients who already had liver diseases, for patients with other serious illness to which drug was appointed for treatment of general diseases, and also at the patients receiving other medicines possessing gepatotoksicheksky action. However some patients had no associated diseases or obvious risk factors concerning damage of a liver. 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. In case of the symptoms assuming developing of hepatitis namely: anorexias, nausea, vomitings, weaknesses, abdominal pains and darkenings of urine, it is necessary to stop immediately treatment and to conduct a research of function of a liver. To patients with increase in activity of "hepatic" enzymes or a disease of a liver in an active phase, or at the postponed toxic damage of a liver owing to reception of other drugs it is not necessary to appoint treatment the drug Orungal® unless the expected advantage justifies risk of damage of a liver. In such cases it is necessary to control activity of "hepatic" enzymes during treatment. Itrakonazol is preferential metabolized 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: data on use of drug for patients with renal failures are limited, at some patients with insufficiency of function of kidneys exposure of an itrakonazol can be lowered. Therefore such patients should appoint drug with care. 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 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 undergone an operation on organ transplantation.

− Patients with the system fungal infections posing a threat of life: owing to pharmacokinetic characteristics of the drug Orungal® in the form of capsules its use 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.

− Use in pediatric practice: as children have not enough clinical data on use of the drug Orungal®, it is recommended to appoint drug to children only if the possible advantage of treatment surpasses potential risk.

− the Women of childbearing age accepting the drug Orungal® need to use adequate methods of contraception throughout all course of treatment up to approach of the first periods after its end.

− Treatment should be stopped when developing peripheral neuropathy which can be connected with reception of capsules of the drug Orungal®.

− At the system candidiases which are presumably caused flukonazol-by resistant strains of Candida it is impossible to assume sensitivity to an itrakonazol, therefore, it is recommended to check sensitivity before therapy itrakonazoly.

− Hearing loss: It was reported about a temporary or resistant hearing loss at the patients accepting итраконазол. In certain cases the hearing loss happened against the background of a concomitant use to quinidine (see sections of "Contraindication" and "Interaction with Other Medicines"). Hearing is usually recovered after the end of therapy by the drug Orungal®, however at some patients the hearing loss is irreversible.

− Ability to conceive: researches on animals did not show existence of reproductive toxicity at an itrakonazol.

− Mucoviscidosis (cystous fibrosis): At patients with a mucoviscidosis (cystous fibrosis) variability of concentration of an itrakonazol in a blood plasma at use of an itrakonazol in the form of solution for intake in a dose of 2,5 mg/kg was observed 2 times a day. As a result, therapeutic equilibrium concentration of an itrakonazol in a blood plasma can not be reached. Equilibrium concentration> 250 ng/ml were reached approximately at 50% of patients 16 years are more senior and were not reached at one patient 16 years are younger. In the absence of the response to therapy by the drug Orungal®, capsules it is necessary to consider the possibility of transition to alternative therapy.

Influence on ability to manage vehicles, mechanisms. The research on studying of influence of Orungal® medicine on ability to manage vehicles and to work with the equipment was not conducted. It is necessary to take into account possibility of side reactions, such as dizziness, a vision disorder and a hearing loss (see. "Side effect"). At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Side effects of drug are systematized concerning each of systems of bodies depending on occurrence frequency, with use of the following classification:

Very often (≥1/10);

Often (≥1/100, <1/10);

Infrequently (≥1/1000, <1/100);

Seldom (≥1/10000, <1/1000);

Very seldom (<1/10000), including isolated cases.

Frequency is not known (it cannot be calculated on the basis of the available data).

The data obtained during clinical trials Safety of the drug Orungal®, capsules it was studied in 107 open and double blind clinical trials with participation of 8499 patients. All 8499 patients at least once accepted the drug Orungal®, capsules then assessment of safety of treatment was carried out.

Infectious and parasitic diseases:

Infrequently: rhinitis, sinusitis, upper respiratory tract infections.

Disturbances from the hemopoietic and lymphatic systems:

Seldom: leukopenia;

Frequency is unknown: neutropenia.

Disturbances from immune system:

Infrequently: hypersensitivity.

Disturbances from a nervous system:

Often: headache;

Seldom: hypesthesia, paresthesia.

Disturbances from an acoustic organ and labyrinth disturbances:

Seldom: a ring in ears.

Disturbances from digestive tract:

Often: abdominal pain, nausea;

Infrequently: dyspepsia, lock, meteorism, diarrhea, vomiting;

Seldom: dysgeusia.

Disturbances from a liver and biliary tract:

Infrequently: hyperbilirubinemia, abnormal liver function.

Disturbances from integuments and a hypodermic fatty tissue:

Infrequently: rash, itch, urticaria.

Disturbances from kidneys and urinary tract:

Seldom: pollakiuria.

Disturbances from reproductive system and mammary glands:

Infrequently: disturbance of a menstrual cycle;

Seldom: erectile dysfunction.

Complications of the general character and reaction in an injection site:

Seldom: edematous syndrome.

The list of the undesirable reactions connected with reception of an itrakonazol which were registered in clinical trials of the drug Orungal® in the form of solution for intake and/or in the form of solution for intravenous administration is given below (except for the side reactions belonging to the category of "an inflammation in the place of an injection" as these side reactions are specific to a dosage form "solution for intravenous administration").

Disturbances from the hemopoietic and lymphatic systems: granulocytopenia, thrombocytopenia.

Disturbances from immune system: anaphylactoid reactions.

Disturbances from a metabolism: hyperglycemia, hyperpotassemia, hypopotassemia, hypomagnesiemia.

Disturbances of mentality: confusion of consciousness.

Disturbances from a nervous system: peripheral neuropathy, dizziness, drowsiness.

Disturbances from cardiovascular system: heart failure, insufficiency of a left ventricle, tachycardia, arterial hypertension, arterial hypotension.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: fluid lungs, dysphonia, cough.

Disturbances from digestive tract: gastrointestinal frustration.

Disturbances from a liver and biliary tract: hepatitis, jaundice, abnormal liver function.

Disturbances from skin and hypodermic fabrics: erythematic rash, hyperhidrosis.

Disturbances from skeletal and muscular and connecting fabric: mialgiya, arthralgia.

Disturbances from kidneys and urinary tract: insufficiency of function of kidneys, urine incontience.

The general frustration and disturbances in an injection site: generalized hypostases, face edema, stethalgia, hyperthermia, pain, fatigue, fever.

Influence on results of laboratory indicators and tool researches: increase in activity of alaninaminotranspherase, increase in activity of aspartate aminotransferase, increase in activity of an alkaline phosphatase in a blood plasma, increase in activity of a lactate dehydrogenase in a blood plasma, increase in concentration of urea of blood, increase in activity gamma глутамилтрансферазы, increase in activity of liver enzymes, an aberration of indicators of the general analysis of urine.

Children. Safety of the drug Orungal®, the capsule, was estimated in 14 clinical trials (4 double blind people, placebo - controlled researches, 9 open researches, and 1 research had an open phase with the subsequent the double blind person) with participation of 165 children aged from 1 year up to 17 years. During the researches it was noted that the most often found side reactions were: headache, vomiting, abdominal pain, diarrhea, abnormal liver function, nausea, urticaria. The nature of the side reactions which are found at children is similar to the fact that it is observed at adult patients; nevertheless, the frequency of side reactions at children is higher.

The side effects registered in the post-registration period (data are obtained on the basis of spontaneous messages) the Presented frequency of side reactions is based on clinical experience of use of the drug Orungal® after registration.

From immune system:

Very seldom: serum disease, Quincke's disease, anaphylactic, anaphylactoid and allergic reactions.

Metabolism disturbances:

Very seldom: gipertriglitseridemiya.

Disturbances from a nervous system:

Very seldom: tremor.

From an organ of sight:

Very seldom: indistinct sight, diplopia.

Disturbances from an acoustic organ and labyrinth disturbances:

Very seldom: resistant or temporary hearing loss.

From cardiovascular system:

Very seldom: chronic heart failure.

From system of a respiratory organs:

Often: asthma.

From digestive tract:

Very seldom: pancreatitis.

From gepatobiliarny system:

Very seldom: crushing toxic damage of a liver (including several cases of an acute liver failure with a lethal outcome).

From integuments and hypodermic fatty tissue:

Very seldom: toxic epidermal necrolysis, Stephens-Johnson's syndrome, acute generalized ekzentematozny пустулез, polymorphic erythema, exfoliative dermatitis, leykotsitoklastichesky vasculitis, alopecia, photosensitivity.

Influence on results of laboratory indicators and tool researches:

Very seldom: increase in activity of a kreatinfosfokinaza of blood.

Interaction with other medicines:

Itrakonazol is preferential metabolized by CYP3A4 isoenzyme. Other medicines which are also metabolized with participation of this isoenzyme or change its activity, can influence pharmacokinetics of an itrakonazol. In a similar way итраконазол can influence pharmacokinetics of medicines which are also metabolized with the participation of this isoenzyme. Itrakonazol treats strong inhibitors of an isoenzyme CYP3A4 and P-glycoprotein. When using an itrakonazol together with other medicines it is recommended to study the application instruction for clarification of a way of metabolism of drug and the solution of a question of need of change of its dose.

Medicines which can reduce concentration of an itrakonazol in a blood plasma. The medicines reducing acidity of a gastric juice (for example, antiacid means, such as aluminum hydroxide, or means suppressing secretion of hydrochloric acid such as antagonists of H2 - histamine receptors and inhibitors of a proton pomp), break absorption of the drug Orungal®, the capsule. These medicines are recommended to be used with care in combination with the drug Orungal®, capsules:

- Itrakonazol is recommended to accept together with acid drinks (such as not dietary Coca) when sharing the medicines reducing acidity of a gastric juice.

- It is recommended to accept the medicines neutralizing hydrochloric acid (for example, aluminum hydroxide), at least in 1 hour prior to or in 2 hours after administration of drug of Orungal®, the capsule.

- At joint reception of medicines it is recommended to control antifungal activity of an itrakonazol and to increase a drug dose at need emergence.

Combined use of an itrakonazol with strong inductors of an isoenzyme CYP3A4 can promote decrease in bioavailability of an itrakonazol and gidroksiitrakonazol to such an extent that efficiency of medicine will decrease. Examples include the following drugs:

• Antibacterial agents: isoniazid, рифабутин, rifampicin.

• Anticonvulsant drugs: carbamazepine, phenobarbital, Phenytoinum.

• Antiviral drugs: эфавиренз, not Virapinum.

Thus, use of strong inductors of an isoenzyme of CYP3A4 together with itrakonazoly is not recommended. It is recommended to avoid purpose of these medicines within two weeks prior to reception of an itrakonazol and during treatment by drug, except for cases when the expected advantage exceeds the potential risk connected with decrease in efficiency of an itrakonazol. At joint reception of medicines it is recommended to control antifungal activity of an itrakonazol and to increase a drug dose at need emergence.

Medicines which can cause increase in concentration of an itrakonazol in a blood plasma. The concomitant use of an itrakonazol and strong inhibitors of an isoenzyme CYP3A4 can lead to increase in bioavailability of an itrakonazol. Examples of strong inhibitors of an isoenzyme of CYP3A4:

• Antibacterial drugs: ciprofloxacin, кларитромицин, erythromycin.

• Antiviral means: дарунавир, strengthened ritonaviry, фосампренавир, strengthened ritonaviry, индинавир, ритонавир.

These medicines are recommended to be used with care together with itrakonazoly. It is recommended to control carefully a condition of the patients accepting итраконазол together with strong inhibitors of an isoenzyme CYP3A4 for early detection of symptoms and signs of strengthening or prolongation of pharmacological effects of an itrakonazol, if necessary the dose decline of an itrakonazol is possible. It is whenever possible recommended to control concentration of an itrakonazol in a blood plasma.

Medicines which concentration in a blood plasma can increase when sharing with itrakonazoly. Itrakonazol and his main metabolite гидроксиитраконазол can break metabolism of medicines, metaboliziruyemy an isoenzyme of CYP3A4 and interfere with transportation of drugs under the influence of a P-glycoprotein. It can lead to increase in plasma concentration of these medicines and/or their active metabolites at joint reception with itrakonazoly. Increase in plasma concentration, in turn, can cause strengthening or prolongation of both therapeutic, and undesirable effects of these medicines therefore there can be potentially life-threatening states. So, increase in concentration of some drugs (терфенадин, астемизол, bepridit, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, сертиндол, left methadone) can lead to increase in an interval-QT and ventricular tachyarrhythmia, including cases of ventricular tachycardia like "pirouette" which belongs to potentially life-threatening states. After the treatment termination plasma concentration of an itrakonazol decreases to almost indefinable within from 7 to 14 days, depending on a dose of drug and duration of treatment. At patients with cirrhosis or those who at the same time accept CYP3A4 enzyme inhibitors decrease in concentration of drug can be even slower. It is especially important during the beginning of performing therapy with use of medicines which metabolism influences итраконазол.

Drugs which plasma concentration can decrease under the influence of an itrakonazol. Simultaneous use of an itrakonazol with non-steroidal anti-inflammatory drug meloksikamy can reduce concentration of a meloksikam in plasma. It is recommended to appoint with care to meloksika along with itrakonazoly, and also carefully to control a clinical condition of the patient an ivozniknoveniye of side effects. In case of need it is necessary to adjust a dose of a meloksikam.

Children. Medicinal interactions are studied only at adults.

Contraindications:

− Hypersensitivity to an itrakonazol or excipients;

− the Concomitant use of drugs of substrates of an isoenzyme of CYP3A4 (see the section "Interaction with Other Medicines"), such, as:

  - левацетилметадон, methadone;

  - Disopyramidum, дофетилид, дронедарон, quinidine;

  - галофантрин;

  - астемизол, мизоластин, терфенадин;

 - ergot alkaloids: dihydroergotamine, ergometrine (эргоновин), ergotamine, methylergometrine (метилэргоновин), элетриптан;

  - иринотекан;

 - лурасидон, midazolam for oral administration, Pimozidum, сертиндол, to triazoles;

 - bepridit, фелодипин, лерканидипин, нисолдипин; - ивабрадин, ранолазин; - эплеренон;

  - цизаприд;

  - ловастатин, симвастатин, аторвастатин;

  - colchicine at patients with abnormal liver functions or kidneys.

− Chronic heart failure now or in the anamnesis (except for therapy of zhizneugrozhayushchy or other dangerous infections. See the section "Special Instructions").

− Intolerance of fructose, deficit of invertase/isomaltase, glyukozo-galaktozny malabsorption.

− Children's age up to 3 years.

− Pregnancy and breastfeeding.

With care:

– at cirrhosis;

– heavy abnormal liver functions and kidneys;

– hypersensitivity to other azoles;

– at elderly patients;

– at children (see also section "Special Instructions").

Overdose:

The symptoms observed at overdose by the drug Orungal®, capsules were comparable to the dozozavisimy side reactions observed at use of usual doses of drug.

Treatment: The specific antidote does not exist. In case of overdose it is necessary to carry out a maintenance therapy, to make a gastric lavage bicarbonate sodium solution, to give absorbent carbon. Itrakonazol does not leave from an organism at a hemodialysis.

Storage conditions:

At a temperature from 15 to 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 100 mg. On 4, 5, 6 and 14 capsules in the blister from PVC and aluminum foil. On 1 blister (on 4, 6 or 14 capsules) or 3 blisters (on 5 capsules) or on 2, 3 or 6 blisters (on 14 capsules) together with the application instruction in a cardboard pack. When packaging at the Russian enterprise CJSC MFPDK BIOTEK on 1, 2, 3 or 6 blisters on 14 capsules in a cardboard pack together with the application instruction.