Expiration date: 02/2025

Structure and Composition: 

The capsules. 1 capsule contains 0.1 g of itraconazole

(Pellets of itraconazole - sufficient amount to obtain the contents of the capsule weight - 0.464 g)

in blisters 5, 6, 7, 10 or 14 pieces. In the paper cartons 1, 2 or 3 or a packaging in cans of 5, 10 or 15 pieces. In the paper cartons 1 bank.

Description pharmaceutical form:

Capsules yellow. The contents of capsules - a spherical micro-granules from light yellow to yellow-colored bezhevatogo.

Characteristic:

Synthetic antifungal broad spectrum triazole derivative.

Pharmacokinetics:

Maximum bioavailability of itraconazole observed inside immediately after a heavy meal when taking the capsules. Plasma Cmax is achieved within 3-4 hours after ingestion. Withdrawal from the plasma phase is 2- End T1 / 2 by 1 to 1.5 days. Chronic administration of the equilibrium concentration is achieved within 1-2 weeks. Itraconazole concentration in the plasma within 3-4 hours after ingestion of 0.4 mg / ml (1 of 100 mg once a day), 1.1 ug / ml (1 of 200 mg once a day) and 2.0 ug / ml ( 200 mg 2 times a day). Binding to plasma proteins - 99.8%. The accumulation of the drug in the keratinous tissues, particularly the skin, approximately 4 times greater than the accumulation in the blood plasma, but it depends on the rate of excretion of regeneration of the epidermis. In contrast, plasma concentrations that are not detectable after 7 days after stopping therapy, therapeutic concentrations persist in the skin for 2-4 weeks after stopping the 4-week course of treatment. Itraconazole is found in nail keratin already 1 week after initiation of treatment and stored for at least 6 months, 3 months after completion of therapy. Itraconazole is also defined in the sebum and to a lesser extent in perspiration.

Itraconazole is well distributed in the tissues that are susceptible to fungal attack. The concentrations in the lungs, kidneys, liver, bone, stomach, spleen and muscle of 2-3 times higher than corresponding concentrations in plasma. Therapeutic concentrations of the vaginal tissues preserved for a further 2 days after 3 days of treatment at a dose of 200 mg per day, and 3 days after 1-day treatment with 200 mg 2 times a day.

Itraconazole is metabolized by the liver with the formation of a large number of metabolites. One of these metabolites is gidroksiitrakonazol which has comparable with itraconazole antifungal activity in vitro. Antifungal drug concentration determined by microbiological method, about 3 times higher than the concentrations measured by HPLC. Excretion in the feces is from 3 to 18% of the dose. Approximately 35% of the dose excreted in urine as metabolites for 1 week.

Description of the pharmacological actions:

It inhibits fungal ergosterol cell membrane, which causes the antifungal effect of the drug.

Itraconazole is active against infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeast fungi and yeasts (Cryptococcus neoformans, Pityrosporum 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, yeast and other fungi and molds.

Indications:

• ringworm
  
• fungal keratitis
  
• onychomycosis caused by dermatophytes and / or yeasts and molds
  
• systemic mycoses: systemic aspergillosis and candidiasis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other systemic or tropical mycoses
  
• candidiasis skin or mucous lesions, including vulvovaginal candidiasis
  
• deep visceral candidiasis
  
• chromophytosis.
  

Contraindications:

Hypersensitivity to the drug or its components.

Carefully:

• childhood
  
• severe heart failure
  
• liver disease (including hepatic insufficiency accompanied)
  
• simultaneous with terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, is metabolized with CYP3A4 enzyme reductase inhibitors of HMG-CoA (simvastatin and lovastatin), triazolam, and midazolam (see. also "Interactions with other medicinal products" section) .
  

Application of pregnancy and breastfeeding:

Based on the results of preclinical studies and due to the fact that research on the use of itraconazole in pregnant women have not been conducted, itraconazole should be administered to pregnant women only in life-threatening systemic fungal infections, where the potential benefits to women justifies the potential risk to the fetus.

Women of childbearing age receiving Irunine, you must use adequate contraception methods during the course of treatment until the onset of the first menstrual period after its completion.

Since a small amount of itraconazole is excreted in human milk, the potential benefits from receiving itraconazole must be weighed against the risk for the baby during breastfeeding. If in doubt, do not breast-feed.

Side effect:

The most frequently reported adverse reactions in connection with the use of itraconazole were the reaction of the gastrointestinal tract, such as dyspepsia, nausea, abdominal pain and constipation. In addition, noted: anorexia, headache, fatigue, reversible elevation of liver enzymes, cholestatic jaundice, hepatitis, menstrual disorders, dizziness and allergic reactions (such as pruritus, rash, urticaria, angioedema), peripheral neuropathy, Stevens syndrome Johnson, alopecia, hypokalemia, edema, congestive heart failure and pulmonary edema, staining of urine in a dark color, hypercreatininemia.

In very rare cases, when applying Irunine developed severe liver toxicity, including cases of acute liver failure with fatal consequences.

Drug Interactions:

1. drugs affecting the metabolism of itraconazole

Concomitant use of itraconazole with rifampicin, rifabutin and phenytoin, which are potential inducers of hepatic enzymes, it is not recommended. Interaction studies with other hepatic enzyme inducers, such as carbamazepine, phenobarbital and isoniazid, have not been conducted, but similar results can be expected.

Since itraconazole is mainly metabolized by the enzyme CYP3A4, potential inhibitors of this enzyme may increase the bioavailability of itraconazole (ritonavir, indinavir, clarithromycin and erythromycin).

2. Effect of itraconazole on the metabolism of other drugs

Itraconazole can inhibit the metabolism of drugs, is transformed with the participation of the enzyme CYP3A4. The result may be increased or prolonging their action, including and side effects.

After the cessation of treatment plasma levels of itraconazole is gradually reduced depending on the dose and duration of treatment (see., "Pharmacokinetics" section).

Because of this reason should not be administered concurrently with itraconazole:

terfenadine, astemizole, mizolastine, cisapride, oral midazolam and triazolam, dofetilide, quinidine, pimozide, inhibitors of HMG-CoA reductase inhibitors (lovastatin and simvastatin).

BPC may have negative inotropic effect which can amplify the same effect exhibited by itraconazole. At the same time taking itraconazole and BPC must be careful, because BPC metabolism can be reduced.

In the case of co-administration with itraconazole must monitor their concentrations in plasma, side effects and the need to reduce the dose of the following drugs: oral anticoagulants such HIV protease inhibitors, ritonavir, indinavir, saquinavir some anticancer drugs such as vinca alkaloids, busulfan , docetaxel, trimetrexate metabolized by the enzyme CYP3A4 CCB (dihydropyridine and verapamil) some immunosuppressive agents: cyclosporine, tacrolimus, sirolimus other drugs: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, rifabutin, methylprednisolone, ebastine, reboxetine.

The interaction of itraconazole with zidovudine and fluvastatin is not revealed. There was no effect of itraconazole on the metabolism of ethinyl estradiol and norethisterone.

in vitro studies have demonstrated a lack of competition between itraconazole and other drugs such as imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine upon binding to plasma proteins.

Dosage and administration:

Inside, after eating, swallowing whole.

Dose and duration of the appointment in a number of indications are shown in Table 1.

Table 1

Testimony	Dose	The duration of the day
Vulvovaginal candidiasis	200 mg 2 times a day	1
	or 200 mg 1 time a day	3
Chromophytosis	200 mg 1 time a day	7 or 15
Dermatomycoses smooth skin	200 mg 1 time a day	7
	100 mg 1 time a day	15
Fungal keratitis	200 mg 1 time a day	21
Oral candidiasis	100 mg 1 time a day	15

Lesions such vysokokeratinizirovannyh areas of the skin, as the hands and feet, require additional treatment within 15 days of 100 mg / day.

The bioavailability of itraconazole when given orally can be reduced in some patients with impaired immune systems, such as in patients with neutropenia, AIDS or transplant. Therefore, it may require doubling the dose.

Onychomycosis

Pulse therapy (see. Table 2).

One course of pulse therapy - 2 caps. Irunine 2 times a day (200 mg, 2 times a day) daily for 1 week.

two courses recommended for the treatment of fungal infections of the nail plate brushes. For the treatment of fungal infections of the nail plate is recommended to stop three courses. The spacing between courses during which need not take the drug is 3 weeks.

Clinical results become apparent after treatment, as regrowth of the nail.

Table 2

Localization of onychomycosis	Weeks
	1st	2nd	3rd	4th	5th	6th	7th	8th	9th
Defeat stop with the defeat of the nail plate or without	1st course	Week-free reception Irunine			2nd course	Week-free reception Irunine			3-? ????
The defeat of the nail plate brushes	1st course	Week-free reception Irunine			2nd course	-			-

Or

Continuous treatment: 2 capsules. per day (200 mg 1 time per day) for 3 months. Withdrawal Irunine of skin and nail tissue is slower than from plasma. Thus, the optimal clinical and mycological effects are reached within 2-4 weeks after the end of treatment for skin infections and 6-9 months after the treatment of nail infections.

Systemic mycoses (recommended dosage and duration of treatment varies depending on the type of infection - see Table 3.).

Table 3

Testimony	Dose	The average duration	Annotation
Aspergillosis	200 mg 1 time per day	2–5 monthes	Increase the dose to 200 mg 2 times a day in case of invasive or disseminated form of the disease
Candidiasis	100–200 mg 1 time per day	from 3 weeks to 7 monthes
Cryptococcosis (except meningitis)	200 mg 1 time per day	from 2 monthes to 1 year	Supportive therapy - 200 mg 1 time per day
Cryptococcal meningitis	200 mg 2 times per day
Histoplasmosis	frpom 200 mg 1 time per day to 200 mg 2 times per day	8 monthes
Sporotrichosis	100 mg 1 time per day	3 monthes
Paracoccidioidomycosis	100 mg 1 time per day	6 monthes
Chromomycosis	100–200 mg 1 time per day	6 monthes
Blastomycosis	from 100 mg 1 time per day to 200 mg 2 times per day	6 monthes

Overdose:

Data not available.

Treatment: Accidental overdose should apply supportive measures. During the first hour - gastric lavage and if necessary, the appointment of activated carbon. Itraconazole not appear in hemodialysis. Any specific antidote does not exist.

Special instructions:

As clinical data itraconazole capsules in children insufficient itraconazole recommended only if the potential benefit outweighs the potential risk.

In the study of / in the dosage form of the drug itraconazole, conducted in healthy volunteers noted bessimtomnoe transient decrease in left ventricular ejection fraction, normalized to the next infusion.

It found that itraconazole has a negative inotropic effect. It reported cases of heart failure associated with taking Irunine. The drug should not be taken in patients with chronic heart failure, or with the presence of this disease in history except in cases where the potential benefit significantly outweighs the potential risk. When an individual assessment of the ratio of benefits and risks should be taken into account such factors as the seriousness of the indications, dosage regimen and individual risk factors for congestive heart failure. Risk factors include the existence of such heart diseases as coronary artery disease, or severe valvular pulmonary disease (obstructive lung disease), kidney failure and other diseases, accompanied by edema. Such patients should be informed about the signs and symptoms of heart failure. Treatment should be given with caution, with the need to monitor the patients to identify the symptoms of congestive heart failure. When they appear Irunine intake should be stopped.

The clinical relevance of data obtained for oral dosage forms is unknown.

BPC may have a negative inotropic effect, which may intensify this effect of itraconazole itraconazole may decrease the metabolism of BPC. At the same time taking itraconazole and BPC must be careful.

At low acidity of gastric absorption of itraconazole is broken. Patients taking antacids (eg, aluminum hydroxide), it is recommended to use them no earlier than 2 hours after taking the capsules Irunine. Patients with achlorhydria or applying H2 histamine receptor blockers or proton pump inhibitors, are advised to take Irunine capsules with acidic beverages.

In very rare cases, when applying Irunine developed severe liver toxicity, including cases of acute liver failure with fatal consequences. In most cases, this occurred with patients who already had liver disease, in patients who received treatment for systemic indications, with other serious medical conditions as well as in patients treated with other drugs that have hepatotoxic effects. Some patients have no obvious risk factors identified in relation to liver damage. Several of these cases occurred in the first month of therapy, and some - in the first week of treatment. In this connection, it is recommended to regularly monitor liver function in patients receiving treatment with itraconazole. Patients should be warned of the need to immediately contact your doctor in case of symptoms, suggesting the occurrence of hepatitis, such as: anorexia, nausea, vomiting, weakness, abdominal pain, and darkening of the urine, in the event of such symptoms should immediately discontinue therapy and to conduct research function liver. Patients with elevated liver enzymes or liver disease in the active phase, or at any adjourned toxic liver damage when taking other medications should not be given treatment Irunine, except in cases where the expected benefit justifies the risk of liver damage. In these cases, during the treatment to monitor the activity of liver enzymes.

Patients with cirrhosis of the T1 / 2 increased slightly liver itraconazole and bioavailability after oral administration was slightly reduced. In this case, it may be necessary dose adjustment. When the duration of receiving more than 1 month is necessary to monitor liver function.

With impaired renal function: in patients with renal insufficiency, the bioavailability of itraconazole may be reduced. In this case, it may be necessary dose adjustment.

The treatment should be discontinued when a neuropathy, which may be associated with the reception Irunine capsules.

There is no evidence of cross-hypersensitivity to itraconazole and other azole antifungal agents. Irunine capsules should be used with caution in patients with hypersensitivity to other azoles.

Patients with impaired immunity (AIDS, conditions after organ transplantation, neutropenia) may need to increase the dose.

Effects on ability to drive and operate machinery

Not observed.