Kanditral

General characteristics. Structure:

Active agent: итраконазол – 100 mg.
 
Excipients: a gipromelloza (a gidroksipropilmetiltsellyuloza E - 5), methylmethacrylate, a demitilaminoetilmetakrilat and butylmethacrylate copolymer (eudragit E - 100), sucrose.

Solid gelatin capsule No. 0: gelatin, the water purified, methylparahydroxybenzoate, пропилпарагидроксибензоат, sodium lauryl sulfate, dyes: a capsule lid – titanium dioxide, dye ferrous oxide black (for drawing a logo of G),
the capsule case – dye crimson (Ponso 4R), dye an azoruby (кармоизин), titanium dioxide (for a text of "canditral").

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. Itrakonazol 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 Candida albicans, Candida glabrata and Candida 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. Time of achievement of the maximum concentration in a blood plasma makes 3-4 h.

Distribution. Equilibrium concentration of an itrakonazol in plasma in 3-4 hours after administration of drug makes 0,4 mkg/ml (at reception of 100 mg once a day), 1,1 mkg/ml (at reception of 200 mg once a day) and 2,0 mkg/ml (at reception of 200 mg two times a day). At long reception equilibrium concentration is reached within 1-2 weeks. Communication 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, a stomach, bones, skeletal muscles by 2-3 times exceeds its concentration in plasma. Accumulation of an itrakonazol in keratinaceous fabrics, especially in skin, by 4 times exceeds it in plasma, and the speed of removal depends on regeneration of epidermis. Unlike concentration in plasma which do not give in to detection in 7 days after the treatment termination therapeutic concentration of an itrakonazol in skin remains within 2-4 weeks after the termination of a 4-week 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 a day and 3 days after the termination of a one-day course of treatment in a dose of 200 mg twice 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 by a liver with formation of active metabolites, one of which - hydroxy-itrakonazol - renders comparable with itrakonazoly antifungal action - in vitro.

Removal. Removal from plasma is two-phase with a final elimination half-life from 24-36ch.
Removal with a stake makes from 3 to 18% of a dose. Removal by kidneys - less than 0,03% of a dose.
About 35% of a dose are allocated in the form of metabolites with urine within 1 week.

Pharmacokinetics in special clinical cases. At patients with a renal failure, and also at some patients with the broken immunity (for example, at AIDS, after organ transplantation or in case of a neutropenia) bioavailability of an itrakonazol can decrease. At patients with cirrhosis bioavailability of an itrakonazol is reduced, the elimination half-life 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 to patients with a cryptococcosis of the central nervous system of Kanditral® 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;
- споротризоз;
- 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	Duration
Vulvovaginal candidiasis	200 mg 2 times in days or 200 mg of 1 times in days	1 day or 3 days
Chromophytosis	200 mg of 1 times in days	7 days
Dermatomycosis of smooth skin	200 mg of 1 times in days or 100 mg of 1 times in days	7 days or 15 days
Defeats of the high-keratinized areas of an integument, such as hands and feet	200 mg 2 times in days or 100 mg of 1 times in days	7 days or 30 days
Oral candidiasis	100 mg of 1 times in days	15 days

Fungal keratitis

200 mg of 1 times in days

21 days Correction of duration of treatment taking into account positive dynamics of a clinical picture is possible

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

The onychomycoses caused by dermatophytes and/or yeast, mold mushrooms
		Doses and duration of treatment
Pulse therapy		One course: daily reception on 200 mg 2 times (2 capsules 2 times in days) within one week. For treatment of a fungal infection 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 onychomycoses	The 1st week.	The 2nd week.	The 3rd week.	The 4th week.	The 5th week.	The 6th week.	The 7th week.	The 8th week.	The 9th week.
Defeat nail plates of feet with defeat or without defeat nail plates of brushes	The 1st	Weeks, free from			The 2nd	Weeks,			The 3rd
	course	Kanditral's reception			course	free			course
						from reception
						Kanditrala
Defeat	The 1st	Weeks, free from			The 2nd
nail	course	Kanditral's reception			course
plates of brushes
Continuous treatment			Doses		Treatment duration
Defeat of nail plates of feet with defeat or without defeat of nail plates of brushes			200 mg in days		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	Notes
Aspergillosis	200 mg of 1 times in days	2-5 months	In case of the invasive or disseminated disease about 200 mg 2 times in days are recommended to increase a dose
Candidiasis	100-200 mg of 1 times in days	from 3 weeks to 7 months	In case of the invasive or disseminated disease about 200 mg 2 times in days are recommended to increase a dose
Cryptococcosis (except meningitis)	200 mg of 1 times in days	of 2 months till 1 year
Cryptococcal meningitis	200 mg two times in days	of 2 months to 1 years	Supporting therapy – see the section "Special Instructions"
Histoplasmosis	from 200 mg of 1 times in days to 200 mg 2 times in days	8 months
Zymonematosis	from 100 mg of 1 times in days to 200 mg 2 times in days	6 months
Sporotrichosis	100 mg of 1 times in days	3 months
Paracoccidioidomycosis	100 mg of 1 times in days	6 months
Chromomycosis	100-200 mg of 1 times in days	6 months

 

Features of use:

- The women of childbearing age accepting Kanditral® 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 of an intravenous dosage form of drug 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 reception of Kanditrala®. Кандитрал® patients should not accept with chronic heart failure or with existence of this disease in the anamnesis except for cases when the possible advantage considerably surpasses potential risk.
- Blockers of calcium channels can render a negative inotropic effect which can strengthen similar effect of an itrakonazol; итраконазол 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.
- 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 hours after reception of Kanditrala®. To patients with an achlorhydria or the applying H2 histamine blockers or inhibitors of a protonew pomp, it is recommended to accept the Kanditrala® capsules with acid drinks.
- Seldom or never at use of Kanditrala® 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 medicines possessing a hepatotoxic action. 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.

- Treatment should be stopped when developing neuropathy which can be connected with reception of the Kanditrala® capsules.
- There are no data on cross hypersensitivity to an itrakonazol and other azolovy antifungal drugs. Кандитрал® 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 Kanditrala® can be required.

Impact on ability to drive the car and to work with the equipment
It was not observed.

Side effects:

- From digestive tract: dyspepsia, nausea, vomiting, loss of appetite, abdominal pain, diarrhea, lock.
- From gepato-biliary 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 hypercreatinemia, coloring of urine in dark color.

Interaction with other medicines:

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

The medicines exerting impact on metabolism of an itrakonazol.
Itrakonazol is generally split by CYP3A4 enzyme. At simultaneous use with rifampicin, rifabutiny, Phenytoinum, carbamazepine, an isoniazid which are powerful inductors of CYP3A4 enzyme, bioavailability of an itrakonazol and hydroxy-itrakonazola considerably decreases that leads to essential reduction of efficiency of drug. Simultaneous use of Kanditrala® with these drugs which are potential inductors of liver enzymes is not recommended.

Powerful inhibitors of CYP3A4 enzyme, such as 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 split by CYP3A4 enzyme. Strengthening or prolongation of their action including side effects can be result of it. After the treatment termination by the drug Kanditral®, concentration of an itrakonazol in plasma decreases gradually depending on a dose and duration of treatment (see the section Pharmacokinetics). It needs to be taken into account at discussion of the inhibiting effect of an itrakonazol to the accompanying medicines.
Examples of such drugs are:
Medicines which it is not recommended to appoint along with the drug Kanditral®:

- blockers of calcium channels - in addition to the possible pharmacokinetic interaction connected with the general way of metabolism with CYP3A4 enzyme participation, blockers of calcium channels can render a negative inotropic effect which amplifies at a concomitant use with the drug Kanditral®.

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);
- the blockers of calcium channels (verapamil and derivatives of dihydropyridine) split by CYP3A4 enzyme;
- some immunosuppressive means (cyclosporine, такролимус, сиролимус (also known as рапамицин);
- some inhibitors of GMG-KOA reductase split by CYP3A4 enzyme (аторвастатин);
some glucocorticosteroids (будесонид, dexamethasone and Methylprednisolonum);
- other drugs: digoxin, carbamazepine, буспирон, alfentanil, to alprazola, brotiozolam, midazolam for intravenous administration, 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 medicines as Imipraminum, propranolol, diazepam, Cimetidinum, indometacin, Tolbutamidum and сульфамеразин at linkng with proteins of plasma.

Contraindications:

Individual hypersensitivity to drug or its components.
Reception of the following medicines, simultaneous with the drug Kanditral®:

- drugs, metaboliziruyemy CYP3A4 enzyme which can increase QT an interval (терфенадин, астемизол, мизоластин, цизаприд, дофетилид, quinidine, Pimozidum, left methadone, сертиндол);
- the inhibitors of GMG-KOA reductase split by CYP3A4 enzyme (симвастатин, ловастатин);
- midazolam and to triazoles (for intake);
- drugs of alkaloids of an ergot (dihydroergotamine, ergometrine, ergotamine and methylergometrine);
- children's age up to 3 years.

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

Use at pregnancy and in the period of a lactation
Pregnant women should appoint the drug Kanditral® 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.

Use in pediatrics
Кандитрал® children should not appoint, except for cases when the expected advantage exceeds possible risk.

Overdose:

Data are absent. At accidental overdose it is necessary to carry out a gastric lavage within the first hour, to appoint absorbent carbon. The hemodialysis is not effective. The specific antidote 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 on 100 mg.
On 4, 6 or 7 capsules in a blister strip packaging. 1 blister strip packaging on 4, 6, 7 capsules or 2 blister strip packagings on 7 capsules together with the application instruction is placed in a cardboard pack.