Rumikoz

General characteristics. Structure:

Active agent: итраконазол 100 mg (pellets of an itrakonazol — 0,464 g) 
 
Excipients: gipromelloza; half-oxameasures (лутрол); starch wheat; sucrose 
 
Gelatinous solid capsule: gelatin; titanium dioxide; dye quinolinic yellow; ferrous oxide red; ferrous oxide black; dye yellow "Sunset"; azoruby.

Pharmacological properties:

Pharmacodynamics. Synthetic antifungal broad-spectrum agent derivative of triazole.
Inhibits synthesis of the ergosterol which is an important component of a cellular membrane of mushrooms.
It is active concerning dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), drozhzhepodobny mushrooms and yeast (Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp., Candida spp., including C. albicans, C. glabrata and C. krusei), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Pseudallescheria boydii, Penicillium marneffei, and also other barmy and mold mushrooms.

Pharmacokinetics. Absorption. At oral administration the maximum bioavailability of an itrakonazol is noted at reception of capsules at once after food. Tmax in plasma is 3–4 h after intake.

Distribution. Css of an itrakonazol in plasma in 3–4 h after administration of drug makes 0,4 mkg/ml (at reception of 100 mg of 1 times a day), 1,1 mkg/ml (at reception of 200 mg of 1 times a day) and 2 mkg/ml (at reception of 200 mg 2 times a day). At long reception of Css it is reached during 1–2 weeks. Linkng with proteins of plasma — 99,8%.
Itrakonazol well gets and is distributed in fabrics and bodies. Concentration of drug in lungs, kidneys, a liver, a spleen, bones, a stomach, skeletal muscles by 2–3 times exceeds the corresponding concentration in plasma. Accumulation of drug in keratinaceous fabrics, especially in skin, approximately by 4 times exceeds accumulation in plasma, and the speed of removal depends on the speed of regeneration of epidermis. Unlike concentration in plasma which does not give in to detection in 7 days after the therapy termination therapeutic concentration in skin remains during 2–4 weeks after the termination of a 4 weeks course of treatment; in a mucous membrane of a vagina — within 2 days after the termination of a 3-day course of treatment in a dose of 200 mg of 1 times a day and within 3 days after the termination of a 1-day course of treatment in a dose of 200 mg 2 times a day. Therapeutic concentration of drug in a keratin of nails is defined by 1 week after an initiation of treatment and remains within 6 months after end of a 3-month course of therapy. Itrakonazol is defined also in a secret grease and sweat glands.

Metabolism. It is metabolized in a liver with formation of active metabolites, one of which — гидроксиитраконазол — has comparable with itrakonazoly antifungal effect of in vitro.

Removal. Removal from plasma is two-phase with final T1/2 — 24–36 h.
Removal with a stake makes from 3 to 18% of a dose, kidneys — less than 0,03% of a dose; about 35% of a dose are allocated in the form of metabolites with urine during 1 week.

Pharmacokinetics in special clinical cases. At patients with a renal failure, and also some patients with the broken immunity (for example AIDS, after organ transplantation, a neutropenia) bioavailability of an itrakonazol can decrease. At patients with cirrhosis bioavailability of an itrakonazol is reduced, T1/2 is increased.

Indications to use:

dermatomycoses;
fungal keratitis;
the onychomycoses caused by dermatophytes and/or yeast and mold mushrooms;
system mycoses:
- system aspergillosis and candidiasis;
- a cryptococcosis, including cryptococcal meningitis (to patients with an immunodeficiency and a cryptococcosis of TsNS Rumikoz® it has to be appointed only in cases if drugs of the first line of treatment are not applicable in this case or are not effective);
- histoplasmosis;
- sporotrichosis;
- paracoccidioidomycosis;
- zymonematosis;
- other system or tropical mycoses;
candidiases with damage of skin and mucous, including vulvovaginal candidiasis;
deep visceral candidiases;
chromophytosis.

Route of administration and doses:

Inside, after food.

Indication	Dose	Use duration, days
Vulvovaginal candidiasis	200 mg 2 times a day 200 mg of 1 times a day	1 3
Chromophytosis	200 mg of 1 times a day	7
Dermatomycoses of smooth skin	200 mg of 1 times a day 100 mg of 1 times a day	7 15
Fungal keratitis	200 mg of 1 times a day	21 Correction of duration of treatment taking into account positive dynamics of a clinical picture is possible
Oral candidiasis	100 mg of 1 times a day	15
Defeats of the high-keratinized areas of an integument, such as hands and feet	200 mg 2 times a day 100 mg of 1 times a day	7 30

Bioavailability of drug at oral administration can be reduced at some patients with the broken immunity, for example at patients with a neutropenia, AIDS or transferred organ transplantation. In these cases double increase in a dose can be required.

The onychomycoses caused by dermatophytes and/or yeast, mold mushrooms. Pulse therapy (see tab. 2). One course pulse therapy consists in daily reception 2 капс. 2 times a day (on 200 mg 2 times a day) during 1 week.

For treatment of fungal infections of nail plates of toes 3 courses are recommended.

For treatment of fungal infections of nail plates of fingers of hands 2 courses are recommended.

The interval between courses makes 3 weeks. Clinical results become obvious after the end of treatment in process of growth of nails.

Localization of an onychomycosis	1st week.	2 weeks.	3 weeks.	4 weeks.	5th week.	6th week.	7th week.	8th week.	9th week.
Nail plates of toes with defeat or without defeat of nail plates of fingers of hands	1st course	Weeks, free from administration of drug of Rumikoz®			2nd course	Weeks, free from administration of drug of Rumikoz®			3rd course
Nail plates of fingers of hands	1st course	Weeks, free from administration of drug of Rumikoz®			2nd course	—

Defeat of nail plates of toes with defeat or without defeat of nail plates of fingers of hands. Continuous treatment — on 2 капс. in day (200 mg of 1 times a day) within 3 months.

Removal of an itrakonazol from skin and nail fabric is carried out more slowly, than from plasma. Thus, the optimum clinical and mycologic effect is reached in 2–4 weeks after the end of treatment at diseases of skin and in 6–9 months after the end of treatment of diseases of nails.

System mycoses

Indication	Dose	Average duration of treatment	Note
Aspergillosis	200 mg of 1 times a day	2–5 months	It is recommended 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	of 3 weeks up to 7 months
Cryptococcosis (except meningitis)	200 mg of 1 times a day	from 2 months to 1 year	—
Cryptococcal meningitis	200 mg 2 times a day	from 2 months to 1 year	—
Histoplasmosis	200 mg 1–2 times a day	8 months	—
Zymonematosis	100 mg of 1 times a day — 200 mg 2 times a day	6 months	—
Sporotrichosis	100 mg of 1 times a day	3 months	—
Paracoccidioidomycosis	100 mg of 1 times a day	6 months	—
Chromomycosis	100–200 mg of 1 times a day	6 months	—

Features of use:

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

At a research in/in a dosage form of an itrakonazol the passing asymptomatic reduction of fraction of emission of a left ventricle normalized before the following infusion of drug was noted.

It is revealed what итраконазол possesses a negative inotropic effect. It was reported about the cases of development of heart failure connected with administration of drug of Rumikoz®. Румикоз® patients should not accept with chronic heart failure or existence of this disease in the anamnesis except for cases when the possible advantage considerably surpasses potential risk.

BKK can render a negative inotropic effect which can strengthen similar effect of an itrakonazol; итраконазол can reduce metabolism of BKK. At a concomitant use of an itrakonazol and BKK it is necessary to be careful.

At patients with a renal failure bioavailability of an itrakonazol can be reduced that can demand dose adjustment.

At the lowered acidity of a stomach absorption of an itrakonazol is broken. To the patients accepting antiacid drugs (for example aluminum hydroxide), it is recommended to use them not earlier than in 2 h after administration of drug of Rumikoz®. Patients with an achlorhydria or the applying H2 blockers of histamine receptors or inhibitors of a proton pomp are recommended to accept drug Rumikoz® capsules with acid drinks.

Seldom or never at use of the drug Rumikoz® crushing toxic damage of a liver, including cases of an acute liver failure with a lethal outcome developed. It happened to patients who already had liver diseases, and also for the patients receiving other HP possessing a hepatotoxic action. Several such cases arose in the 1st month of therapy, and some — in 1 week of treatment. In this regard it is regularly recommended to control function of a liver at the patients receiving therapy itrakonazoly.

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

There are no data on cross hypersensitivity to an itrakonazol and other azolovy antifungal drugs. Румикоз® in capsules patients should appoint with care with hypersensitivity to other azoles.

At patients with the broken immunity (AIDS, after organ transplantation, a neutropenia) increase in a dose of the drug Rumikoz® can be required.

Influence on ability to manage vehicles and to work with mechanisms. It was not observed.

Side effects:

- From a GIT: dyspepsia, nausea, vomiting, loss of appetite, abdominal pain, diarrhea, lock.
- From gepatobiliarny system: reversible increase in activity of hepatic transaminases, hepatitis; very seldom — crushing toxic damage of a liver, including an acute liver failure with a lethal outcome.
- From a nervous system: headache, dizziness, peripheral neuropathy.
- Allergic reactions: skin rash, a skin itch, a small tortoiseshell, a Quincke's disease, it is rare — a multiformny exudative erythema (Stephens-Johnson's syndrome).
- From integuments: alopecia, photosensitivity.
- Other: disturbances of a menstrual cycle, a hypopotassemia, an edematous syndrome, congestive heart failure and a fluid lungs, a giperkreatininemiya, coloring of urine in dark color.

Interaction with other medicines:

The HP exerting impact on absorption of an itrakonazol

The drugs reducing acidity of a gastric juice reduce absorption of an itrakonazol.

The HP exerting impact on metabolism of an itrakonazol

Itrakonazol is generally split by CYP3A4 enzyme. At simultaneous use of an itrakonazol with rifampicin, rifabutiny, Phenytoinum, carbamazepine, an isoniazid which are the powerful inductors CYP3A4, bioavailability of an itrakonazol and gidroksiitrakonazol considerably decreases that leads to essential reduction of efficiency of drug. Simultaneous use of Rumikoza® with these drugs which are potential inductors of liver enzymes is not recommended.

Powerful inhibitors of CYP3A4 enzyme (for example ритонавир, индинавир, кларитромицин, erythromycin) can increase bioavailability of an itrakonazol.

Influence of an itrakonazol on metabolism of other HP

Itrakonazol can inhibit metabolism of the drugs split by CYP3A4 enzyme. Strengthening or prolongation of their action, including and side effects can be result of it. After the treatment termination by the drug Rumikoz® concentration of an itrakonazol in plasma decreases gradually, depending on a dose and duration of treatment (see. "Pharmacokinetics"). It needs to be taken into account at discussion of the inhibiting effect of an itrakonazol to the accompanying HP.

HP which it is not recommended to appoint along with the drug Rumikoz®

BKK. In addition to the possible pharmacokinetic interaction connected with the general way of metabolism with participation of CYP3A4, BKK enzyme can render a negative inotropic effect which amplifies at a concomitant use with the drug Rumikoz®.

Drugs at which co-administration it is recommended to watch their concentration in plasma, action, side effects. If necessary the dose of these drugs should be reduced:

- peroral anticoagulants;

- HIV protease inhibitors (ритонавир, индинавир, саквинавир);

- some antineoplastic drugs (alkaloids of a periwinkle pink, бусульфан, dotsetakset, триметрексат);

- BKK split by CYP3A4 enzyme (verapamil and derivatives of dihydropyridine);

- some immunosuppressive means (cyclosporine, такролимус, сиролимус (also known as рапамицин);

- some inhibitors of GMG-KOA-reduktazy split by CYP3A4 enzyme (аторвастатин);

- some GKS (будесонид, dexamethasone and Methylprednisolonum);

- other drugs: digoxin, carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, midazolam for in/in introductions, рифабутин, эбастин, ребоксетин, цилостазол, Disopyramidum, элетриптан, галофантрин, репаглинид.

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

Influence of an itrakonazol on metabolism of ethinylestradiol and Norethisteronum was not noted.

The researches in vitro showed lack of interaction between itrakonazoly and such HP as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum and сульфамеразин, at linkng with proteins of plasma.

Contraindications:

individual hypersensitivity to drug or its components;
concomitant use with the drug Rumikoz® of the following HP:
- drugs, metaboliziruyemy CYP3A4 enzyme which can increase QT interval (терфенадин, астемизол, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, left methadone, сертиндол);
- the GMG-KOA-reduktazy inhibitors split by CYP3A4 enzyme (симвастатин, ловастатин);
- midazolam and to triazoles (for intake);
- drugs of alkaloids of an ergot (dihydroergotamine, ergometrine, ergotamine and methylergometrine).

With care: children's age; heavy heart failure; liver diseases (including followed by a liver failure); chronic renal failure.

Use at pregnancy and feeding by a breast
Pregnant women should appoint the drug Rumikoz® only in life-threatening cases if the expected advantage for the woman exceeds potential risk for a fruit. At appointment in the period of a lactation it is necessary to stop breastfeeding.

Overdose:

Data are absent.

Treatment: at accidental overdose it is necessary to carry out a gastric lavage within the first hour, if necessary — purpose of absorbent carbon. Itrakonazol is not brought at a hemodialysis. The specific antidote of drug does not exist.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules, 100 mg. In a blister strip packaging from the film of PVC and printing aluminum foil varnished on 5 or 6 pieces 1 packaging on 6 pieces or 3 packagings on 5 pieces in a pack from a cardboard.