Orungal

General characteristics. Structure:

Active agent – итраконазол, 10 mg.

Excipients: гидроксипропилбетадекс 400 mg; Acidum hydrochloricum concentrated 3,76 мкл; propylene glycol 100 мкл; sodium hydroxide to pH 1,7-1,9; sodium saccharinate of 0,6 mg; sorbitol solution of 70% 190 мкл; fragrance Cherry 1 - 0,25 mg; fragrance of Cherry 2 - 0,5 mg; fragrance Caramel - 0,2 mg; the water purified to 1,0 ml.

Description. Yellow or light orange solution with a cherry smell.

Pharmacological properties:

Pharmacodynamics. The synthetic antifungal broad-spectrum agent containing итраконазол derivative triazole. Itrakonazol inhibits synthesis of ergosterol of a cellular membrane of mushrooms that causes antifungal effect of drug. Itrakonazol is active concerning the infections caused by mushrooms:

- dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); - drozhzhepodobny mushrooms and yeast (Candida spp., including C. albicans, S. of 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 Zygomycetes (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-demetilazu 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

Itrakonazol is well soaked up at oral administration. The maximum concentration in plasma are reached in 2,5 hours after oral administration of solution of drug. 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 decreases to 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 solution reception inside. The maximum concentration in a blood plasma of an itrakonazol is reached within 2,5 hours after reception on an empty stomach of solution for intake. Absolute bioavailability of an itrakonazol at administration of drug with food – about 55%, at solution reception on an empty stomach bioavailability of an itrakonazol increases by 30%.

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

Distribution. The most part of an itrakonazol in plasma contacts proteins (99,8%), generally albumine (for a metabolite of an itrakonazol – a gidroksiitrakonazol – linkng with proteins makes 99,6%). Also affinity of an itrakonazol to lipids is noted. Only 0,2% of an itrakonazol in plasma are presented in the untied form. Itrakonazol well gets into fabrics: concentration in lungs, kidneys, a liver, bones, a stomach, a spleen and muscles in two – three times are higher, than the corresponding concentration in a blood 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. Itrakonazol is exposed to intensive metabolism in a liver with formation of a large number of metabolites. As shown in the researches in vitro, итраконазол it is metabolized mainly with participation of an isoenzyme of CYP3A4. The main metabolite is гидроксиитраконазол which in vitro possesses antifungal action, comparable with action of an itrakonazol. Concentration of this metabolite in plasma are almost twice higher, than the corresponding concentration of an itrakonazol.

Removal. About 35% of an itrakonazol in the form of inactive metabolites within a week are excreted with urine and about 54% – with a stake. Renal excretion of initial substance and its active metabolite makes less than 1% of the dose entered intravenously. From 3 to 18% of a dose of initial substance are allocated with a stake. As redistribution of an itrakonazol from keratinaceous fabrics is insignificant, removal of an itrakonazol from these fabrics, is connected with regeneration of epidermis. Unlike a blood plasma, concentration in skin remains within 2 – 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 3-month course of treatment.

Special groups of patients.

Abnormal liver function.

Itrakonazol is preferential metabolized in a liver. According to data of a research of pharmacokinetics at the patients having cirrhosis statistically reliable decrease in average value of an indicator of Cmax (47%) and double increase in an elimination half-life (37 ± 17 hours in comparison with 16 ± 5 hours) an itrakonazola in comparison with healthy people was observed. Nevertheless, patients had an identical general system influence of an itrakonazol, (AUC) with cirrhosis and at healthy examinees. Data on pharmacokinetics of an itrakonazol at patients with cirrhosis at prolonged use of an itrakonazol are absent.

Renal failure.

The data concerning use of an itrakonazol for intake 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 the system influence of an itrakonazol calculated on AUC was slightly lower in comparison with that at patients with normal function of kidneys. Considerable influence of a hemodialysis or long peritoneal dialysis on indicators of pharmacokinetics of an itrakonazol is not revealed (Tmax, Cmax and AUC0-8ch).

After single intravenous administration average value of a final elimination half-life of an itrakonazol at patients with a renal failure easy (clearance of creatinine of 50-79 ml/min.), average (clearance of creatinine of 20-49 ml/min.) or heavy degree (the clearance of creatinine <20 ml/min.) was similar to that at healthy volunteers (range of average values of 42-49 hours in comparison with 48 hours at patients with renal failures and healthy volunteers respectively). The system influence of an itrakonazol calculated on AUC was lower at patients with moderate ivyrazhenny renal failures approximately for 30% and 40%, respectively, in comparison with patients at whom function of kidneys is not broken. There are no data on long use of an itrakonazol by patients with renal failures. 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 oral administration 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 while the insignificant interrelation between age of patients and values of volume of distribution of drug, Cmax and a final elimination half-life was in rare instances observed were not registered. The established clearance of an itrakonazol and its volume of distribution depend on the body weight of patients.

Гидроксипропилбетадекс.

Bioavailability of the gidroksipropilbetadeks applied as solvent of an itrakonazol in solution to intake on average is 0,5% lower, than at reception only a gidroksipropilbetadeksa. Low bioavailability of a gidroksipropilbetadeks does not depend on meal and frequency rate of reception.

Indications to use:

− treatment of candidiasis of an oral cavity and/or gullet at HIV-positive patients and patients with an immunodeficiency;

− prevention of system fungal infections patients with malignant diseases of blood or at patients at bone marrow transplantation with high probability have neutropenias (less than 500 cells / мкл).

Route of administration and doses:

Inside.

To accept on an empty stomach, it is desirable to refuse meal at least within 1 hour after reception of an itrakonazol. Solution it is necessary to rinse a mouth within 20 seconds and then to swallow it. After that it is not necessary to rinse a mouth water.

Treatment of candidiasis of an oral cavity and/or gullet: 200 mg (2 measured cups) a day in one or two receptions within 1 week. In the absence of positive effect in 1 week it is necessary to continue treatment one more week.

Treatment of candidiasis of an oral cavity and/or gullet, at resistance to a flukonazol: 100–200 mg (1-2 measured cups) 2 times a day for 2 weeks. In the absence of positive effect after 2 weeks of use of drug treatment is continued for 2 more weeks. In the absence of positive effect it is possible to accept a daily dose of 400 mg no more than 14 days.

Prevention of fungal infections: Inside, 5 mg/kg of body weight a day in two steps. During clinical trials preventive treatment was begun just before treatment by cytostatics and usually in one week prior to the procedure of transplantation. Administration of drug of Orungal® is continued before recovery of number of neutrophils (not less than 1000 cells / мкл).

Special groups of patients.

Children. Data, about drug Orungal® use, solution for intake, for treatment of children are limited. Drug Orungal® use, solution, for treatment of children is not recommended, except for cases when the expected advantage surpasses possible risk. Prevention of fungal infections: there are no data on efficiency of use of drug for children with a neutropenia. Data on safety of the itrakonazol applied in a dose of 5 mg/kg of body weight at reception 2 times a day are limited. Side effects, such as diarrhea, an abdominal pain, fervescence, vomiting, mukozit were observed more often at children, than at adults. Nevertheless, connection of emergence of these by-effects with administration of drug of Orungal® is definitely not established.

Elderly patients. Data on drug Orungal® use, solution for treatment of patients of advanced age are limited. It is recommended to use the drug Orungal® for treatment of patients of this category, only if the expected advantage of treatment exceeds potentsialnyerisk. At the same time, 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 an itrakonazol for intake at 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 an itrakonazol for intake at 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

Use at pregnancy and during breastfeeding.

Pregnancy. Орунгал® it should not be applied at pregnancy, except for cases, life-threatening and if the expected positive effect for mother surpasses possible harm for a fruit. In preclinical trials it was shown what итраконазол gets through a placenta at rats.

Data on use of Orungal® solution during pregnancy are not enough. During a clinical use of drug after registration cases of congenital anomalies were noted. Such cases included disturbances of development of sight, a skeleton, urinogenital and cardiovascular systems, and also chromosomal disturbances and multiple malformations. However, whether Orungal® solution use is an origin of these disturbances, authentically it is not established. Epidemiological data concerning influence of the drug Orungal® in the first trimester of pregnancy, generally at the patients receiving short-term therapy concerning vulvovaginal candidiases did not reveal the increased risk of development of congenital anomalies in comparison with the control group which was not affected by any of the known teratogens. 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.

Breastfeeding. As итраконазол can get into breast milk, in need of use during breastfeeding, the women using the drug Orungal® should stop breastfeeding.

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 an acute heart failure connected with administration of drug of Orungal®. At a daily dose of an itrakonazol of 400 mg more frequent developing of heart failure was observed, at smaller daily doses of such pattern it was not revealed; the risk of developing of an acute heart failure is presumably proportional to a daily dose. Орунгал® patients should not accept with an acute 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 such factors as gravity of indications, the mode of dosing and individual risk factors of developing of an acute heart failure into account. Risk factors include existence of diseases of cardiovascular system, such as coronary heart disease or defeats of valves; diseases of lungs, such as obstructive pulmonary diseases; the renal failure or other diseases which are followed by hypostases. Such patients need to be informed on signs and symptoms of an acute heart failure. Treatment has to be carried out with care, during treatment it is necessary to control symptoms and symptoms of an acute heart failure. At emergence of similar signs or symptoms during a course of treatment administration of drug of Orungal® needs to be stopped.

Life-threatening arrhythmias of heart and/or sudden death were noted at patsiyet 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.

Data concerning existence of cross hypersensitivity to an itrakonazol and other azoles are limited. In the presence of a rezistention 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.

Mucoviscidosis (cystous fibrosis). At patients with a mucoviscidosis (cystous fibrosis) it was observed variabelnostkontsentration of an itrakonazol in a blood plasma at constant reception of solution in a dose of 2,5 mg/kg of body weight two times a day. As a result, therapeutic equilibrium concentration of an irakonazol in a blood plasma can not be reached.

Use in pediatric practice. As clinical data on use of an itrakonazol in the form of solution for intake for treatment of children are not enough, it is recommended to appoint solution of an itrakonazol to children only if the possible advantage surpasses potential risk. According to separate messages, итраконазол it is applied in pediatric practice to prevention of fungal infections at patients with a neutropenia in a dose of 5 mg/kg of body weight at reception 2 times a day. Side effects, such as diarrhea, an abdominal pain, fervescence, vomiting, mukozit were observed more often than at adults. Nevertheless, connection of emergence of these undesirable phenomena with administration of drug of Orungal® is definitely not established.

Use for patients of advanced age. As clinical data on use of solution of an itrakonazol for intake by patients of advanced age are not enough, it is recommended to appoint solution of an itrakonazol such patient only if the possible advantage surpasses potential risk. At the choice of a dose of drug for treatment of this category of patients it is recommended to consider depression of function of a liver, kidneys and heart, and also existence of associated diseases or reception of other medicines.

Influence on function of a liver.

Seldom or never at use of the drug Orungal® 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 patients to whom drug was appointed for treatment of the general diseases having other serious illness, 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 case of such symptoms it is necessary to stop immediately therapy and to conduct a research of function of a liver.

Abnormal liver function. Data on use of an itrakonazol for intake for treatment of patients with abnormal liver functions are limited. It is necessary to appoint drug with care of this category of patients. It is recommended to watch carefully a condition of patients with abnormal liver functions at treatment itrakonazoly. At joint purpose of other medicines, metaboliziruyemy CYP3A4 enzyme, it is recommended to take into account the fact that in clinical trial of single oral administration of capsules of an itrakonazol by patients with cirrhosis increase in an elimination half-life of drug was observed. Itrakonazol is preferential metabolized in a liver. As patients with abnormal liver functions have a full elimination half-life of an itrakonazol несколькоувеличен, it is recommended to control concentration of an itrakonazol in a blood plasma and if necessary to adjust a drug dose.

Renal failure. As at patients with a renal failure the full elimination half-life of an itrakonazol is a little increased, it is recommended to control concentration of an itrakonazol in a blood plasma and if necessary to adjust a drug dose.

Use for patients with a heavy neutropenia. In view of pharmacokinetic properties of Orungal® solution (see the section "Pharmacokinetics"), and also the increased risk of bystry development of system candidiases, at patients with a heavy neutropenia it is not necessary to apply Orungal® solution as means of initial therapy.

Cross rezistention.

At the system candidiases which are presumably caused by flukonazol-resistant strains of Candida it is impossible to assume sensitivity to an itrakonazol, therefore, it is recommended to check sensitivity before therapy itrakonazoly. Treatment should be stopped when developing peripheral neuropathy which can be connected with Orungal® solution reception.

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 was irreversible.

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

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 the section "Side effect"). At emergence of the described undesirable phenomena it is necessary to refrain from vypolneniyaukazanny types of activity.

Side effects:

Side reactions 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®, solution for intake was studied in clinical trials with participation of 889 patients participating in 6 double blind people and 4 open clinical trials. Each of 889 patients at least once accepted the drug Orungal®, solution for intake then assessment of safety of treatment was carried out.

Disturbances from the hemopoietic and lymphatic systems:

Infrequently: leukopenia, thrombocytopenia, neutropenia.

Disturbances from immune system:

Infrequently: hypersensitivity.

Disturbances from a metabolism:

Infrequently: hypopotassemia.

Disturbances from a nervous system:

Often: headache, dizziness;

Infrequently: peripheral neuropathy, paresthesia, hyperesthesia;

Frequency is unknown: hypesthesia.

Disturbances from an acoustic organ and balance:

Infrequently: a ring in ears.

Disturbances from cardiovascular system:

Infrequently: heart failure.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

Often: cough.

Disturbances from digestive tract:

Often: abdominal pain, vomiting, nausea, diarrhea, dysgeusia, dyspepsia;

Infrequently: lock.

Disturbances from a liver and biliary tract:

Infrequently: hyperbilirubinemia, abnormal liver function.

Disturbances from integuments and a hypodermic fatty tissue:

Often: rash; Infrequently: itch, urticaria.

Disturbances from skeletal and muscular system and connecting fabric:

Infrequently: mialgiya, arthralgia.

Disturbances from bodies of a reproductive system and mammary glands:

Infrequently: disturbance of a menstrual cycle.

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

Often: hyperthermia;

Infrequently: 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 capsules 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 dannyepobochny reactions are specific to a dosage form "solution for intravenous administration").

Infectious diseases: sinusitis, upper respiratory tract infections, rhinitis.

Disturbances from the hemopoietic and lymphatic systems: granulocytopenia.

Disturbances from immune system: anaphylactoid reactions.

Disturbances from a metabolism: hyperglycemia, hyperpotassemia, hypomagnesiemia.

Disturbances of mentality: confusion of consciousness.

Disturbances from a nervous system: drowsiness.

Disturbances from cardiovascular system: left ventricular failure, tachycardia, arterial hypertension, arterial hypotension.

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

Disturbances from digestive tract: gastrointestinal frustration, meteorism.

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

Disturbances from integuments and a hypodermic fatty tissue: erythematic rash, hyperhidrosis.

Disturbances from kidneys and urinary tract: renal failure, pollakiuria, urine incontience.

Disturbances from bodies of a reproductive system and mammary glands: erectile dysfunction.

Complications of the general character and reaction in an injection site: generalized hypostases, face edema, stethalgia, pain, fatigue, fever.

Influence on laboratory indicators: 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 in a blood plasma, increase in activity of a gamma glutamiltransferaza, increase in activity of liver enzymes, an aberration of indicators of the general analysis of urine.

Children. Safety of the drug Orungal®, solution for intake was estimated in five open clinical trials with participation of 250 children aged from 6 months up to 14 years. During the researches it was noted that the most often found side reactions were: vomiting, a hyperthermia, diarrhea, mukozit, rash, an abdominal pain, nausea, increase in arterial pressure, cough. 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 (1). 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 reactions.

Disturbances from a metabolism:

Very seldom: gipertriglitseridemiya.

Disturbances from a nervous system:

Very seldom: tremor.

From an organ of sight:

Very seldom: vision disorders, including indistinct sight and a diplopia.

From an acoustic organ and balance:

Very seldom: resistant or temporary hearing loss.

From cardiovascular system:

Very seldom: chronic heart failure.

From respiratory system, bodies of a thorax and a mediastinum:

Very seldom: asthma.

From digestive tract:

Very seldom: pancreatitis.

From a liver and biliary tract:

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, photosensitization;

Influence on laboratory indicators:

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

(1) data are obtained on the basis of spontaneous messages.

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. 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 drug 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 use 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 effect of an itrakonazol, at emergence of need 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 at a concomitant use with itrakonazoly. Itrakonazol and his main metabolite гидроксиитраконазол can break exchange of medicines, metaboliziruyemy an isoenzyme of CYP3A4 and interfere with transportation of drugs under the influence of a P-glycoprotein. It can give a kuvelicheniya of 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 reactions of these medicines. Reception together with itrakonazoly medicines, metaboliziruyemy an isoenzyme of CYP3A4 and capable to extend QT interval on the electrocardiogram, can be contraindicated as it can lead to development of ventricular tachyarrhythmias, including arrhythmia on the pirouette type which is potentially life-threatening state. After the treatment termination plasma concentration of an itrakonazol decreases to almost indefinable within 7 – 14 days, depending on a dose of drug and duration of treatment. At patients with cirrhosis or at the patients who are at the same time accepting 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 and emergence 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;

− Deficit of invertase/isomaltase, intolerance of fructose, glyukozo-galaktozny malabsorption;

− 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;

 − inhibitors of GMG-KOA reductase, such, as ловастатин, симвастатин, аторвастатин;

  − colchicine at patients with abnormal liver functions or kidneys.

− Clinically expressed ventricular dysfunction: congestive heart failure now or in the anamnesis (except for therapy of zhizneugrozhayushchy or other dangerous infections. See the section "Special Instructions");

− Pregnancy, except for life-threatening cases, and the breastfeeding period (see the section "Use at Pregnancy and during Breastfeeding").

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

With care:

− at a liver failure;

− at cirrhosis;

− at a chronic renal failure;

− at an acute heart failure;

− at hypersensitivity to other azoles; − at children and elderly patients (see also section "Special Instructions").

Overdose:

The symptoms observed at overdose by the drug Orungal®, solution for intake 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:

To store at a temperature not above 25 °C in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intake of 10 mg/ml. On 150 ml of solution in a bottle of dark glass, with the screw-on cover with the mechanism of protection against accidental opening by children. 1 bottle complete with a measured cup on 10 ml in a cardboard pack together with the application instruction.