Itrakonazol

General characteristics. Structure:

Active ingredient: 100 mg of an itrakonazol.

Excipients: the oksipropilmetiltsellyuloza, sucrose, eudrazhit E-100, gelatin, глицерол, нипагин, нипазол, polyethyleneglycol, titanium dioxide, sodium lauryl sulfate, dyes (E133, E122).

Effective drug for treatment of onychomycoses, thanks to good tolerance and a broad spectrum of activity use of an itrakonazol at onychomycoses is possible even without definition of a specific type of the activator which caused it. Differs in the broad spectrum of activity, the longest impact on a fungus. Immunity to an itrakonazol practically does not develop

Pharmacological properties:

Pharmacodynamics. Derivative triazole, synthetic antifungal means, active concerning a wide range of activators. Inhibits synthesis of ergosterol of a cellular membrane of mushrooms. It is active concerning dermatophytes (Trichophyton spp., Epidermophyton floccosum, Microsporum spp.), barmy mushrooms of Candida spp. (including S. albicans), mold mushrooms (Cryptococcus neoformans, Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatidis).

Indications to use:

Dermatomycoses; the onychomycoses caused by dermatophytes and/or yeast and mold mushrooms; a candidiasis with damage of skin and mucous membranes, including vulvovaginal candidiasis; chromophytosis; system mycoses, including a system aspergillosis and candidiasis, a cryptococcosis (including cryptococcal meningitis), histoplasmosis, a sporotrichosis, a paracoccidioidomycosis, a zymonematosis; visceral candidiases; fungal keratitis.

Therapy of systemic fungal infections when therapy antifungal preparatm of the first line is contraindicated or inefficient (that can be connected with nonsensitivity of the activator or to a drug toksichnosye).

Maintenance therapy at patients with AIDS for prevention of a recurrence of the main fungal infection.

Use of an itrakonazol for prevention of fungal infections at a long neutropenia is allowed, in case of impossibility of use of standard therapy.

Route of administration and doses:

Features of use:

Reactions of cross hypersensitivity. Patients should appoint capsules with care with hypersensitivity to other azoles.

Influence on cordial activity. Itrakonazol possesses a negative inotropic effect. It was reported about the cases of chronic heart failure connected with administration of drug. Pi to a daily dose of 400 mg of an itrakonazol observed more frequent developing of heart failure; 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.

Drug 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 the following factors are taken into account: gravity of indications, the mode of dosing and individual risk factors of developing of heart failure (an ischemic heart disease, the defeat of valves, obstructive pulmonary diseases, a renal failure and other diseases which are followed by hypostases). Patients should 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 needs to be stopped.

Blockers of calcium channels can render a negative inotropic effect which can strengthen similar effect of an itrakonazol. Itrakonazol can reduce metabolism of blockers of calcium channels. At a concomitant use of an itrakonazol and blockers of calcium channels it is necessary to be careful because of the increased risk of congestive heart failure.

Influence on function of a liver. Seldom or never at use of an itakonazol 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 a hepatotoxic 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. Itrakonazol's appointment 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 has to be carried out after ratio assessment risk advantage. In case of purpose of drug, during treatment it is necessary to control activity of "hepatic" enzymes.

Reduced acidity of a gastric juice. At reduced acidity of a gastric juice absorption of an itrakonazol from capsules is broken. The patients accepting antiacid drugs (for example, aluminum hydroxide) are recommended to use them not earlier than in 2 hours after reception of capsules of Itrakonazol. The patients accepting the drugs reducing acidity of a gastric juice (blockers of H2-histamine receptors or inhibitors of a proton pomp) are recommended to accept итраконазол with acid drinks for absorption normalization.

Use for elderly patients is possible if the potential advantage of treatment surpasses the possible risk connected with administration of drug.

To patients with an hourly and liver failure drug is appointed with care.

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. Hearing is usually recovered after the end of therapy by drug, however at some patients the hearing loss is irreversible.

Patients with an immunodeficiency. At some patients with the broken immunity, for example, at patients with a neutropenia, patients with AIDS or undergone an operation on organ transplantation, bioavailability of an itrakonazol at oral administration can be reduced. The attending physician needs 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.

Patients with the system fungal infections posing a threat of life. It is not recommended to appoint drug to start treatment of the system mycoses posing a threat for life of patients.

Neytropatiya. When developing peripheral neuropathy which can be connected with reception of capsules of drug Itrakonazol treatment should be stopped.

Disturbance of metabolism of carbohydrates. Contains sucrose. Patients with rare hereditary diseases should not apply: inborn galactosemia, deficit of lactase, sprue of a glucose/galactose or insufficiency of enzyme of invertase-isomaltase.

Drug should not be used at pregnancy except for cases of treatment of zhizneugrozhayushchy infections when the expected advantage for the woman exceeds potential risk for a fruit.

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

As итраконазол can get into breast milk, in need of use in the period of a lactation, it is necessary to stop breastfeeding.

It is not recommended to appoint drug to children up to 18 years, due to the lack of sufficient clinical data about use for children.

In need of control of motor transport and work with mechanisms during use of drug it is necessary to consider possibility of side effects, such as dizziness, a vision disorder and a hearing loss.

Side effects:

Frequency of undesirable reactions which were observed or during conduct of clinical trials or were received from spontaneous messages on development of undesirable reactions is defined as follows: often (> 1/100 - <1/10); infrequently (> 1/1000 - <1/100); seldom (> 1/10 000 - <1/1000); very seldom (<1/10 000), it is unknown (frequency cannot be determined by the data which are available for today).

Disturbances from hemopoietic and lymphatic system: seldom – a leukopenia; very seldom – a neutropenia, thrombocytopenia.

Disturbances from immune system: very seldom – a serum disease, a Quincke's disease, anaphylactic and anaphylactoid reactions.

Disturbances from a metabolism: very seldom – a gipertriglitseridemiya, a hypopotassemia.

Disturbances from a nervous system: not often – a headache, dizziness, paresthesia; seldom – a hypesthesia; very seldom – peripheral neuropathy.

Disturbances from organs of sight: seldom – indistinct sight; very seldom – a diplopia.

Disturbances from acoustic organs and labyrinth disturbances: seldom – a ring in ears; very seldom – a resistant or temporary hearing loss.

Disturbances from CCC: very seldom - chronic heart failure.

Disturbances from system of a respiratory organs: very seldom – a fluid lungs, an otdyshka.

Disturbances from a GIT: often – an abdominal pain, nausea; infrequently – vomiting, diarrhea, a lock, dyspepsia, a dysgeusia, a meteorism; very seldom – pancreatitis.

Disturbances from gepatobiliarny system: infrequently – a hyperbilirubinemia, increase in level of nuclear heating plant and ALT; seldom – increase in activity of liver enzymes; very seldom – crushing toxic damage of a liver (including several cases of an acute liver failure with a lethal outcome), hepatitis.

Disturbances from skin and hypodermic fabrics: often – rash; infrequently – urticaria, an itch, hypersensitivity, an alopecia; very seldom – a toxic epidermal necrolysis, Stephen-Johnson's syndrome, acute generalized exanthematous пустулез, a polymorphic erythema, exfoliative dermatitis, a leykotsitoklastichesky vasculitis, a small tortoiseshell, a photosensitivity.

Disturbances from skeletal and muscular system: very seldom – a mialgiya, an arthralgia.

Disturbances from kidneys and urinary tract: seldom – a pollakiuria; very seldom – an urine incontience.

Disturbances from reproductive system: infrequently – disturbance of a menstrual cycle; very seldom – erectile dysfunction.

General frustration: infrequently – an edematous syndrome; very seldom – a hyperthermia.

Interaction with other medicines:

The medicines exerting impact on absorption and metabolism of an itrakonazol. The medicines reducing acidity of a gastric juice reduce absorption of an itrakonazol.

Itrakonazol is generally metabolized with participation of an isoenzyme of CYP3A4. At interaction of an itrakonazol with powerful inductors of an isoenzyme CYP3A4 (rifampitsinay, rifabutiny and Phenytoinum) bioavailability of an itrakonazol and hydroxy-itrakonazola considerably decreases that leads to essential reduction of efficiency of drug and, respectively, simultaneous use with these drugs is not recommended. It is possible to expect emergence of similar effect at interaction of an itrakonazol with other inductors of microsomal enzymes of a liver (carbamazepine, phenobarbital and an isoniazid). Powerful igibitor of an isoenzyme of CYP3A4 (ритонавир, индинавир, кларитромицин and erythromycin) can increase bioavailability of an itrakonazol.

Influence of an itrakonazol on metabolism of other medicines. Itrakonazol can inhibit metabolism of the drugs which are substrates of isoenzymes CYP3A4 that can cause strengthening or prolongation of action including side effects. At simultaneous use of other drugs it is necessary to consider information concerning their metabolism. After the termination of treatment of concentration of an itrakonazol in plasma decrease gradually depending on a dose and duration of treatment that it is necessary to take into consideration at assessment of the inhibiting effect of an itrakonazol on metabolism of at the same time appointed drugs. When carrying out a course of treatment itrakonazoly it is impossible to appoint drugs at the same time:
- астемизол, bepridit, цизаприд, дофетилид, left methadone, мизоластин, Pimozidum, quinidine, сертиндол, терфенадин which use together with drug Itrakonazol can lead to increase in concentration of these substances in plasma that in turn can cause increase in an interval of Q-T and in rare instances Bouveret's ventricular disease like "pirouette" (torsade des pointes);
- midazolam for intravenously introduction and to triazoles;
- metaboliziruyemy CYP3A4 isoenzyme GMG-KOA-reduktazy inhibitors, such, as аторвастатин, симвастатин and ловастатин;
- drugs of alkaloids ergot, such, as дегидроэрготамин, ergometrine, ergotamine and methylergometrine;
- элетриптан;
- нисолдипин.

Since in addition to possible pharmacokinetic interaction with participation of a metabolizing isoenzyme of CYP3A4, blockers of slow calcium channels can render a negative inotropic effect which can exponentiate similar effect of an itrakonazol, it is necessary to apply with care итраконазол together with blockers of slow calcium channels.

At co-administration of the following medicines with itrakonazoly, monitoring of their concentration in plasma, action, side effects is necessary, if necessary to reduce a dose:
- indirect anticoagulants;
- HIV protease inhibitors, such, as ритонавир, индинавир, саквинавир;
- some antineoplastic drugs: the drugs containing alkaloids of the Periwinkle pink (including Vincristinum, vinblastine), бусульфан, доцекатен, триметрескат;
- the blockers of slow calcium channels metabolizing an isoenzyme CYP3A4, such as derivatives of dihydropyridine and verapamil;
- some immunodepressive means: cyclosporine, такролимус, сиролимус;
- some metaboliziruyemy CYP3A4 isoenzyme GMG-KOA-reduktazy inhibitors (аторвастатин);
- some glucocorticosteroids, such, as будесонид, dexamethasone, флутиказон and Methylprednisolonum;
- digoxin (through R-glycoprotein inhibition);
- other drugs: alfentantit, to alprazola, brotiozolam, буспирон, carbamazepine, цилостазол, Disopyramidum, эбастин, элетриптан, fentanyl, галофантрин, midazolam for intravenous administration, ребоксетин, репаглинид, рифабутин.

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

The researches in vitro showed lack of interaction between itrakonazoly and such drugs as имипрамид, пропранол, diazepam, Cimetidinum, indometacin, Tolbutamidum and Sulfadiazinum at linkng with proteins of plasma.

Contraindications:

Hypersensitivity to an itrakonazol or close to it on chemical structure to azolny connections; simultaneous use of a terfenadin, astemizol, mizolastin, tsizaprid, dofetilid, quinidine, Pimozidum, simvastatin, lovastatin, midazolam, triazolam, dihydroergotamine, ergometrine (ergonovin), ergotamine and methylergometrine (metilergonovin), eletriptan; nisoldipina; pregnancy (except cases of treatment of zhizneugrozhayushchy infections when the expected advantage for the woman exceeds potential risk of a fruit). 

Overdose:

Symptoms: the overdose is followed by strengthening of side effects.

Treatment: a gastric lavage (during 1 h after administration of drug), absorbent carbon. Itrakonazol is not brought at dialysis, there is no specific antidote.

Storage conditions:

In the place protected from moisture and light at a temperature not above 25 °C. To store in the places protected from children. Period of storage 2 years.

Issue conditions:

According to the recipe

Packaging:

On 7 capsules in blister strip packagings. On 1, 2 or 3 blister strip packagings in a cardboard pack together with the application instruction.