Itrakon

General characteristics. Structure:

Active ingredient: itraconazole;

1 capsule contains итраконазол, pellets in terms of итраконазол 100 mg;

excipients: gipromeloza (gidroksipropilmetiltsellyuloza (Е 5)), sucrose;

the gelatin capsule contains dyes: azoruby (Е 122) and yellow decline of FCF (Е 110).

Pharmacological properties:

Pharmacodynamics. Itrakonazol – derivative triazole. Active concerning the infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeast Cryptococcus neoformans, Pityrosporum spp., Candida spp., including S. of albicans, C. glabrata and S. of krusei, Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis and other kinds of yeast and mushrooms. The researches in vitro showed what итраконазол reduces synthesis of ergosterol which is an important component of a cellular membrane of a mushroom, the inhibition of its synthesis provides antifungal effect.

Pharmacokinetics. The maximum biological availability of an itrakonazol at intake is observed at use right after reception of high-calorific food. The maximum level in plasma is reached in 3-4 hours. Removal from plasma two-phase with a final elimination half-life from 1 to 1,5 days.

At prolonged use stable concentration is reached in 1-2 weeks. Stable concentration of an itrakonazol in plasma in 3-4 hours after reception of medicine reach 0,4 mg/ml (at reception of 100 mg of 1 times a day), 1,1 mg/ml (at reception of 200 mg of 1 times a day) and 2,0 mg/ml (at reception of 200 mg 2 times a day).

Binding of an itrakonazol proteins of plasma makes 99,8%.

Accumulation of an itrakonazol in keratinaceous fabrics, especially in skin, is 4 times higher, than in plasma, and its removal depends on regeneration of epidermis. Therapeutic levels of drug in skin after the termination of a 4 weeks course of treatment remain within 2-4 weeks. Concentration of an itrakonazol reveal in a keratin of nails in a week after an initiation of treatment, remain at least within 6 months after end of a 3-month course of therapy.

Itrakonazol also contains in separated sebaceous glands and in smaller quantity – in sweat.

Concentration level in lungs, kidneys, a liver, bones, a stomach, a spleen, muscles by 2-3 times exceeds the corresponding concentration in plasma.

Therapeutic concentration in tissues of a vagina remain within 2 days after the termination of a 3-day course of treatment in a dose of 200 mg a day within 3 days after end of a one-day course of treatment in a dose of 200 mg twice a day.

Itrakonazol is substantially split in a liver with formation of a large number of metabolites. One of such metabolites is hydroxy-itrakonazol which has in vitro comparative with itrakonazoly antifungal action.

Removal with a stake makes from 3 to 18% of the accepted dose, kidneys – less than 0,03% of a dose. About 35% of a dose are removed in the form of metabolites with urine within 1 week.

Pharmaceutical harakterist

Main physical and chemical properties: the case of the capsule of pink color, a lid – blue color. Capsule contents – granules from almost white till cream color, spherical shape.

Indications to use:

The mycoses caused by activators, sensitive to an itrakonazol:
vulvovaginal candidiasis;
dermatological/ophthalmologic fungus diseases: dermatomycosis, chromophytosis, fungal keratitis; oral candidiasis;
the onychomycoses caused by dermatophytes and/or yeast;
system mycoses: a system aspergillosis or candidiasis, a cryptococcosis (including cryptococcal meningitis): to the immunoweakened patients and all patients with a cryptococcosis of the central nervous system Itrakon is appointed only in case of inefficiency of treatment by other antifungal drugs;
histoplasmosis, sporotrichosis, paracoccidioidosis, zymonematosis and other system mycoses which meet extremely seldom, or tropical mycoses.

Route of administration and doses:

Apply inside. It is necessary to use capsules to optimum absorption of drug Itrakon right after reception of high-calorific food.

It is necessary to swallow of capsules entirely.

Vulvovaginal candidiasis

200 mg 2 times a day 1 day or 200 mg of 1 times a day 3 days.

Dermatological/ophthalmologic diseases
Chromophytosis: 200 mg of 1 times a day 7 days.
Dermatomycoses: 200 mg of 1 times a day 7 days or 100 mg of 1 times a day 15 days.

At defeat of sites with considerable degree of keratinization (for example, an epidermophitia of hands and a foot) treatment by doses of 200 mg twice a day within 7 days or 100 mg a day within 30 days is necessary.
Oral candidiases: 100 mg of 1 times a day 15 days.

Bioavailability of an itrakonazol at use inside can be reduced at some patients with defects of immune system, for example, at patients with a neutropenia, patients with AIDS or with transplanted organs. In such cases the doubled dose can be necessary.
Fungal keratitis: 200 mg of 1 times a day for 21 days.

The onychomycoses caused by dermatophytes and/or yeast

Localization of onychomycoses	WEEKS
	1	2-3-4	5	6-7-8	9
Defeat of nail plates on toes, both with defeat on hands, and without it	On 200 mg 2 times a day	Not to accept Itrakon	On 200 mg 2 times a day	Not to accept Itrakon	On 200 mg 2 times a day
Defeat of nail plates only on hands	On 200 mg 2 times a day	Not to accept Itrakon	On 200 mg 2 times a day	-	-

Or continuous treatment:

on 2 capsules a day (200 mg a day) within 3 months.

Removal of an itrakonazol from tissues of skin or nails comes more slowly, than from plasma. Thus optimum clinical and mycologic effects are reached in 2-4 weeks after end of a course of treatment of infections of skin and in 6-9 months after completion of treatment of infections of nail plates.

System mycoses

Indications to use	Dosages	Average duration of treatment	Note
Aspergillosis	200 mg of 1 times in days	2-5 months	Increase in a dose up to 200 mg two times a day in case of the invasive or disseminated disease
Candidiasis	100-200 mg of 1 times a day	of 3 weeks to 7 months
Cryptococcosis (without symptoms of meningitis)	200 mg of 1 times in days	of 2 months till 1 year
Cryptococcal meningitis	2 strike 200 mg in days	of 2 months till 1 year	The supporting treatment (see. "Features of use")
Histoplasmosis	from 200 mg of 1 times a day to 200 mg 2 strike in days	8 months
Sporotrichosis	100 mg of 1 times in days	3 months
Paracoccidioidomycosis	100 mg of 1 times in days	6 months	Patients with AIDS have not enough data on efficiency of the specified dosing mode
Chromomycosis	100-200 mg of 1 times a day	6 months
Zymonematosis	from 100 mg of 1 times a day to 200 mg 2 times a day	6 months

Features of use:

Drug contains sugar that should be considered at appointment as its sick diabetes mellitus.

Use with other medicines. At reduced acidity of a stomach absorption of an itrakonazol in intestines worsens. Patients who along with Itrakon use drugs for decrease in acidity (such, as aluminum hydroxide) have to adhere a minimum of a two-hour break between receptions of these medicines. To patients with an achlorhydria, for example, sick AIDS or that which apply H2 blockers or inhibitors of a proton pomp Itrakon with drinks like stake is recommended to accept capsules.

Considering pharmacokinetic features of drug, Itrakon in capsules is not recommended for primary therapy of the medical emergencies caused by system fungal infections.

At patients with AIDS who were treated for system mycoses, such as a sporotrichosis a zymonematosis, histoplasmosis or a cryptococcosis (including cryptococcal meningitis) and which are in risk group of development of a recurrence, need of the supporting treatment has to be considered by the doctor.

Women of reproductive age who accept capsules Itrakon should apply well-tried remedies of contraception during all course of treatment before the first periods after its end.

Dysfunctions of heart. It is known what итраконазол has a negative inotropic effect. It was reported about cases of the congestive heart failure connected using Itrakon. Drug should not be used to patients with congestive heart failure or with existence of this disease in the anamnesis except for cases when the expected advantage considerably exceeds potential risk. At individual assessment of a ratio of advantage/risk it is necessary to consider such factors as indications, the mode of dosing and individual risk factors of developing of congestive heart failure. Risk factors include existence of heart diseases, such as coronary heart disease or defeat of valves; serious illness of lungs, such as obstructive damages of lungs; a renal failure or other diseases which are followed by hypostases. Such patients need to be informed on symptoms of congestive heart failure. Treatment should be carried out with care. During treatment it is necessary to control symptoms of congestive heart failure. At emergence of these symptoms during a course of treatment Itrakon's use should be stopped.

It is necessary to be careful at simultaneous use of an itrakonazol and blockers of calcium channels.

Abnormal liver function. At use of an itrakonazol cases of a heavy hepatotoxic, including an acute fatal liver failure very seldom meet. The recorded by-effects are observed at patients with liver diseases in the anamnesis, or at those which were treated according to system indications and/or accepted hepatotoxic drugs. Some of these cases were observed within the first month of treatment, including in the first weeks. Therefore it is desirable to carry out monitoring of function of a liver at patients who accept Itrakon. Patients need to be warned about need of the urgent address to the doctor in case of signs or symptoms of hepatitis, namely: anorexias, nausea, vomitings, increased fatigue, abdominal pain or dark coloring of urine. In the presence of these symptoms it is necessary to stop urgently treatment and to conduct a research of hepatic functions. Patients with the increased level of liver enzymes, an active disease of a liver or that which had cases of hepatic toxicity at use of other drugs are recommended not to begin treatment, except those cases when the expected result exceeds risk of development of disturbances. In such cases monitoring of liver enzymes is necessary.

Bioavailability of drug at oral administration at patients with cirrhosis decreases a little therefore dose adjustment can be necessary.

Renal failure. Bioavailability of an itrakonazol at oral administration at patients with a renal failure can be reduced. In this case the question concerning dose adjustment can be considered.

Neuropathy. Treatment should be stopped when developing neuropathy which can be connected using capsules Itrakon.

Patients of advanced age. As clinical data on use of an itrakonazol for patients of advanced age are not enough therefore such patients can appoint drug only in that case when the expected advantage of treatment considerably exceeds potential risk.

Prevention at patients with a neutropenia. In clinical trials diarrhea was the most frequent side effect of an itrakonazol. Such disorder of digestive tract can lead to decrease in absorption and can change microbiological flora, potentially promoting fungal colonization. It is necessary to be careful, stopping treatment in such cases.

Cross sensitivity. Information on cross sensitivity between itrakonazoly and other azolovy antifungal drugs is absent. Nevertheless, patients should appoint with care drugs with hypersensitivity to other drugs of an azolovy row.

Hearing loss. There were messages about temporary or a resistant hearing loss at the patients accepting итраконазол. In certain cases the hearing loss happened against the background of simultaneous use to quinidine which is contraindicated (see the section "Contraindications"). Hearing is usually recovered after drug withdrawal, however some patients had an irreversible hearing loss.

Ability to influence speed of response at control of motor transport or work with other mechanisms

Considering that sensitive patients at use of drug can have side reactions (dizziness and others), for the period of administration of drug it is necessary to refrain from control of vehicles and performance of other works demanding concentration of attention.

Side effects:

The most widespread side reactions:

from digestive tract: dyspepsia, nausea, abdominal pain, swelling, lock;

from the central nervous system: headache;

allergic reactions: itch, rash, urticaria, Quincke's disease, Stephens-Johnson's syndrome, rhinitis, sinusitis, upper respiratory tract infections, congestive heart failure and fluid lungs.

It was extremely seldom reported about the following side effects:

Lymphatic system and blood: leukopenia, neutropenia, thrombocytopenia.

Immune system: serum disease, anaphylactic, anaphylactoid reactions.

Metabolic disturbances: gipertriglitseridemiya, hypopotassemia.

Nervous system: peripheral neuropathy, paresthesia, hypesthesia, dizziness.

Organ of sight: vision disorders, inclusive with a diplopia, feeling of "veil" before eyes.

Hearing and vestibular mechanism: the sonitus, tinnit, a temporary or constant hearing loss.

Digestive tract: vomiting, diarrhea, disgeziya.

Gepato-biliarnaya system: a heavy hepatotoxic (including isolated cases of an acute and fatal liver failure), hepatitis, reversible increase in activity of liver enzymes.

Skin and hypodermic fabrics: toxic epidermal necrolysis, multiformny erythema, exfoliative dermatitis, letskotsitoplastichesky vasculitis, alopecia, photosensitivity.

Musculoskeletal system and connecting fabric: mialgiya, arthralgia.

Kidneys and urinary tract: pollakiuria, urine incontience.

Reproductive system: disturbance of a menstrual cycle, erectile dysfunction.

General disturbances: hypostases.

Interaction with other medicines:

Medicines which influence metabolism of an itrakonazol.

At simultaneous use with rifampicin, rifabutiny and Phenytoinum bioavailability of an itrakonazol and hydroxy-itrakonazola decreases that leads to considerable reduction of efficiency of drug. Thus, simultaneous use of an itrakonazol with these drugs which are potential inductors of enzymes is not recommended. A research of interactions of an itrakonazol with other inductors of enzymes, such as carbamazepine, phenobarbital and isoniazid, it was not conducted, but similar interactions can be observed.

As итраконазол it is split preferential by CYP3A4 enzyme, potential inhibitors of this enzyme can increase bioavailability of an itrakonazol, for example, ритонавир, индинавир, кларитромицин and erythromycin.

Influence of an itrakonazol on metabolism of other medicines.

Itrakonazol can oppress metabolism of medicines which are split by enzymes like CYP3A4 cytochrome (see sections of "Contraindication"). Blockers of calcium channels can cause a negative inotropic effect which can strengthen similar effect of an itrakonazol; итраконазол can reduce metabolism of blockers of calcium channels.

It is careful to apply итраконазол along with blockers of calcium channels.

Medicines at which purpose control of level of their concentration in a blood plasma is necessary action and side effects (at their joint appointment with itrakonazoly the dose of the specified drugs if necessary should be reduced):
peroral anticoagulants;
HIV protease inhibitors. Such, as ритонавир, индинавир, саквинавир;
some antineoplastic drugs, such as alkaloids of a periwinkle of pink (Vinca), бусулфан, dotsetakset and триметрексат;
blockers of calcium channels which are split by CYP3A4 enzyme, such as dihydropyridine and verapamil;
some immunosuppressive means: cyclosporine, такролимус, рапамицин (it is also known as сиролимус);
some glucocorticosteroids, such, as будесонид, dexamethasone, Methylprednisolonum;
digoxin (through R-glycoprotein inhibition);
other drugs: carbamazepine, буспирон, alfentanil, fentanyl, цилостозол, Disopyramidum, галофантрин, to alprazola, brotiozolam, midazolam IV, рифабутин, эбастин, ребоксетин, репаглинид, loperamide.

Interaction of an itrakonazol with a zidovudine and fluvastatiny is not revealed.

Influence of an itrakonazol on metabolism of ethinylestradiol and noretisterin was not observed.

Influence on binding of proteins.

The researches in vitro confirmed otsustvy interactions at linkng with proteins of plasma between itrakonazoly and such drugs as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum, Sulfamethazinum.

Contraindications:

Hypersensitivity to an itrakonazol or to any of drug excipients.

Simultaneous use:
the drugs which are metabolized with participation of CYP3A4 enzyme and capable to increase an interval of QT, such as астемизол, bepridit, цизаприд, дофетилид, левацетилметадол (levometadit), мизоластин, Pimozidum, quinidine, сертиндол and терфенадин. Simultaneous use can lead to the increased level of this substrate in a blood plasma and cause lengthening of an interval of QT and in isolated cases bidirectional ventricular tachycardia;
drugs, metaboliziruyemy with participation of CYP3A4 enzyme of inhibitors     of GMG-KOA reductase, such, as аторвастатин, ловастатин and симвастатин;
triazolam and peroral midazolam;
drugs of alkaloids of an ergot, such as dihydroergotamine, ergometrine (эргоновин), ergotamine and methylergometrine (метилэргоновин);
eletriptana;
nisoldipina.

It is not necessary to use drug to patients with ventrikulyarny dysfunction, such as the acute heart failure (AHF) or OSN in the anamnesis, except for treatment of life-threatening or other serious infections (see the section "Features of Use").

It is not necessary to use drug during pregnancy in the absence of vital indications.

Overdose:

Messages on cases of overdose are absent. If there was an accidental overdose, it is necessary to take the supporting measures. Within the first hour after intake it is necessary to wash out a stomach. If it is justified, it is possible to appoint absorbent carbon. Itrakonazol it is impossible to remove by a hemodialysis. There is no specific antidote.

Use during pregnancy or feeding by a breast

Clinical experience of use of Itrakon for treatment of pregnant women is limited therefore during pregnancy drug can be used only in case of system mycosis which threatens life if the expected advantage for mother exceeds potential risk for a fruit.

Very insignificant quantity of an itrakonazol is distinguished in breast milk therefore during feeding by a breast it is necessary to compare possible risk for the child with the expected advantage for mother. In doubtful cases of mother it is necessary to stop feeding by a breast.

Children

As clinical data on use of an itrakonazol for children are not enough, it is recommended to appoint drug to patients of this age category only in that case when the expected advantage of treatment considerably exceeds potential risk.

Storage conditions:

Period of validity: 3 years. Not to use drug after the termination of the period of validity specified on packaging. To store in protected from light and the place, unavailable to children, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

On 5 capsules in the blister. On 3 blisters enclosed in a pack.

On 6 capsules in the blister enclosed in a pack.