Eszol film-coated tablets 100 mg blister No. 10

Instructions Eszol film-coated tablets 100 mg blister No. 10

Composition

active ingredient: itraconazole;

1 tablet contains 100 mg of itraconazole;

excipients: spherical sugar, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone K 30, low-substituted hydroxypropylcellulose, sodium starch glycolate (type A), colloidal anhydrous silica, magnesium stearate, Opadry II 85G54039 pink coating: partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycols, lecithin, red iron oxide (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: capsule-shaped tablets, coated with a pink shell, with the logo "ITR 100" on one side.

Pharmacotherapeutic group

Antifungal drugs for systemic use. ATX code J02A C02.

Pharmacological properties

Pharmacodynamics

Itraconazole is a triazole derivative with a broad spectrum of activity. In vitro studies have shown that itraconazole inhibits the synthesis of ergosterol in fungal cells. Ergosterol is an important component of the fungal cell membrane, and inhibition of its synthesis provides an antifungal effect.

For itraconazole, breakpoints have only been established for Candida spp. For superficial mycotic infections (CLSI M27-A2 breakpoints have not been established using the EUCAST methodology). The CLSI breakpoints are: susceptible ≤ 0.125, susceptible dose-dependent 0.25–0.5, resistant ≥ 1 μg/ml. Breakpoints have not been established for mycelial fungi.

In vitro studies have shown that itraconazole inhibits the growth of a wide range of fungi pathogenic to humans at concentrations usually ≤ 1 μg/ml. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Candida spp., including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.,), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Coccidiodes immitis, Pseudallescheria boydii, Penicillium marneffei and other species of yeasts and fungi.

Candida krusei, Candida glabrata, and Candida tropicalis are generally the least susceptible Candida species, and some isolates demonstrate resistance to itraconazole in vitro.

The main types of fungi not inhibited by itraconazole are zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., and Absidia spp.), Fusarium spp., Scedosporium proliferans, and Scopulariopsis spp.

Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. Mechanisms described include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 that result in reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of a transporter that results in increased efflux of itraconazole from fungal cells (i.e., removal of itraconazole from its target). Cross-resistance among azoles has been observed within Candida species, but resistance to one member of the class does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics

General pharmacokinetic characteristics.

Peak plasma concentrations of itraconazole are reached within 2 to 5 hours after oral administration. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after multiple administration. Steady-state concentrations are generally reached within 15 days with Cmax values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after 100 mg once daily, 200 mg once daily and 200 mg twice daily, respectively. The terminal half-life of itraconazole varies from 16 to 28 hours after a single dose and increases to 34–42 hours after multiple doses. After discontinuation of treatment, itraconazole concentrations decline to levels that are almost undetectable in plasma within 7–14 days, depending on the dose and duration of treatment. The mean plasma clearance of itraconazole after intravenous administration is 278 ml/min. Due to saturable hepatic metabolism, clearance of itraconazole decreases at higher doses.

Absorption.

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations are reached within 2–5 hours after oral administration. The absolute bioavailability of itraconazole is 55%. Maximum oral bioavailability is achieved when a high-calorie meal is consumed immediately after administration.

The absorption of itraconazole tablets is reduced in patients with reduced gastric acidity, patients taking drugs that suppress gastric acid secretion (H2-receptor antagonists, proton pump inhibitors), or in patients with achlorhydria caused by certain diseases (see sections "Special instructions" and "Interaction with other medicinal products and other types of interaction"). Absorption of itraconazole on an empty stomach in such patients is increased if Eszol tablets are used with drinks with increased acidity (e.g. non-diet cola). When a single dose of 200 mg of Eszol on an empty stomach with non-diet cola was used after taking ranitidine, an H2-receptor antagonist, the absorption of itraconazole was comparable to that after taking Eszol tablets alone.

Most of itraconazole binds to plasma proteins (99.8%), with albumin being the main binding component (99.6% for the hydroxymetabolite). Itraconazole also has a high affinity for lipids. Only 0.2% of itraconazole in the blood remains unbound. The apparent volume of distribution of itraconazole is quite large (> 700 l), which suggests its extensive distribution in tissues: concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were 2-3 times higher than those in plasma. The accumulation of itraconazole in keratinous tissues, especially in the skin, was 4 times higher than that in plasma. The concentration in cerebrospinal fluid is much lower than in plasma, but efficacy against infections localized in the cerebrospinal fluid has been demonstrated.

Biotransformation.

Itraconazole is extensively metabolized in the liver to form a large number of metabolites. One of these metabolites is hydroxyitraconazole, which has comparable antifungal activity to itraconazole in vitro. Plasma concentrations of hydroxyitraconazole are approximately 2-fold higher than those of itraconazole.

According to in vitro studies, CYP3A4 is the main enzyme involved in the metabolism of itraconazole.

Breeding.

Approximately 35% of itraconazole is excreted as inactive metabolites in the urine and approximately 54% in the feces. Renal excretion of the parent drug is less than 0.03% of the dose, while excretion of unchanged drug in the feces varies from 3% to 18%. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Linearity/nonlinearity.

Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are reached within 15 days, with Cmax and AUC values 4–7 times higher than after a single dose. The mean elimination half-life is 40 hours after repeated doses.

Special categories of patients.

Liver failure.

Itraconazole is primarily metabolized in the liver. A pharmacokinetic study using a single dose of 100 mg itraconazole was conducted in healthy and cirrhotic subjects. No clinically significant difference in AUC was observed between the two groups. In cirrhotic subjects, a clinically significant decrease in mean Cmax (47%) and a 2-fold increase in the half-life of itraconazole (37 ± 17 vs. 16 ± 5 hours) were observed. Although total itraconazole concentrations, based on AUC, were comparable in both groups.

There are no data available on the long-term use of itraconazole in patients with cirrhosis.

Kidney failure.

Data on the use of oral itraconazole in patients with renal impairment are limited. A pharmacokinetic study using a single dose of 200 mg itraconazole was conducted in patients with renal impairment (uremia, hemodialysis, long-term ambulatory peritoneal dialysis). In uremic patients with a mean creatinine clearance of 13 ml/min × 1.73 m2, the AUC-based concentration was slightly lower compared to healthy volunteers. This study did not demonstrate any significant effect of hemodialysis or long-term ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0-8h). Plasma concentration-time profiles showed significant intersubject variability.

There are no data available on the long-term use of itraconazole in patients with renal impairment. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxyitraconazole.

Children.

Data on the use of oral itraconazole in children are limited. Clinical pharmacokinetic studies in children and adolescents aged 5 months to 17 years were conducted with oral itraconazole (capsules). Individual doses ranged from 1.5 to 12.5 mg/kg/day, administered once or twice daily. There was no significant relationship between itraconazole AUC and total clearance and patient age, but a weak relationship was observed between patient age, volume of distribution, Cmax, and terminal elimination of itraconazole. Apparent clearance and volume of distribution were dependent on patient weight.

Indication

vulvovaginal candidiasis; lichen planus; dermatomycoses caused by itraconazole-sensitive pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), e.g. tinea pedis, tinea inguinale, tinea corporis, tinea palmaris; oropharyngeal candidiasis; onychomycoses caused by dermatophytes and/or yeasts; histoplasmosis; systemic mycoses (in cases where first-line antifungal therapy cannot be used or in case of ineffectiveness of treatment with other antifungal drugs, which may be due to the underlying pathology, insensitivity of the pathogen or toxicity of the drug): aspergillosis and candidiasis; Cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with central nervous system (CNS) cryptococcosis; maintenance therapy in patients with AIDS to prevent relapse of existing fungal infection.

Itraconazole should be prescribed for the prevention of fungal infection in patients with prolonged neutropenia in cases where standard therapy is insufficient.

Contraindication

Itraconazole is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.

Concomitant use of itraconazole and CYP3A4 substrates is contraindicated. Concomitant use may result in increased plasma concentrations of these medicinal products, which may lead to increased or prolonged therapeutic and adverse reactions and potentially life-threatening conditions. For example, increased concentrations of these medicinal products may lead to QT prolongation and ventricular tachyarrhythmias, including ventricular fibrillation, a potentially fatal arrhythmia. These medicinal products are listed in the section “Interaction with other medicinal products and other forms of interaction”.

Itraconazole is contraindicated in patients with ventricular dysfunction, such as congestive heart failure, or a history of congestive heart failure, except for the treatment of life-threatening infections in pregnancy (see section "Special warnings and precautions for use").

Itraconazole should not be used during pregnancy, except for the treatment of life-threatening conditions (see section "Use during pregnancy or breastfeeding"). Women of childbearing potential should use effective contraception during treatment with itraconazole and until the end of the menstrual cycle after treatment.

Interaction with other medicinal products and other types of interactions

Itraconazole is primarily metabolized by cytochrome CYP3A4. Other drugs that are metabolized by this pathway or modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. Itraconazole, in turn, may also affect the pharmacokinetics of other substances. Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein. When used concomitantly with other drugs, the Summary of Product Characteristics of these drugs should also be consulted for information on the metabolic pathways and the possible need for dose adjustment.

Drugs that may reduce itraconazole plasma concentrations

Medicines that reduce stomach acidity (acid-neutralizing medicines such as aluminium hydroxide or acid-suppressing medicines such as H2-receptor antagonists and proton pump inhibitors) affect the absorption of itraconazole from capsules. Caution should be exercised when using the following medicines and itraconazole tablets at the same time:

When itraconazole is used concomitantly with antacids, itraconazole should be taken with acidic beverages such as non-diet cola; antacids (e.g., aluminum hydroxide) should be taken at least 1 hour before or 2 hours after itraconazole; antifungal activity should be monitored and the dose of itraconazole increased if necessary.

Concomitant use of itraconazole with potent CYP3A4 enzyme inducers results in a decrease in the bioavailability of itraconazole and hydroxyitraconazole, resulting in a significant reduction in treatment efficacy. These drugs include:

antibacterials: isoniazid, rifabutin (also in the subsection "Medicines whose plasma concentration is increased by itraconazole"), rifampicin; anticonvulsants: carbamazepine (also in the subsection "Medicines whose plasma concentration is increased by itraconazole"), phenobarbital, phenytoin; antivirals: efavirenz, nevirapine.

Concomitant use of potent CYP3A4 inducers with itraconazole is not recommended. The above-mentioned drugs should not be initiated 2 weeks before, during, or for 2 weeks after treatment with itraconazole, unless the potential benefit clearly outweighs the potential risk. The level of antifungal activity should be carefully monitored and the dose of itraconazole increased if necessary.

Drugs that increase the concentration of itraconazole in blood plasma.

Potent inhibitors of the CYP3A4 enzyme may increase the bioavailability of itraconazole. For example:

antibacterials: ciprofloxacin, clarithromycin, erythromycin; antivirals: darunavir, ritonavir-boosted, fosamprenavir, ritonavir-boosted, indinavir, ritonavir (also in the subsection "Medicines whose plasma concentration is increased by itraconazole").

These drugs should be used with caution when used concomitantly with itraconazole. Such patients should be carefully monitored for symptoms of increased or prolonged pharmacological effects of itraconazole and, if necessary, the dose of itraconazole should be reduced. It is recommended to monitor the concentration of itraconazole in the blood plasma.

Itraconazole and its major metabolite hydroxyitraconazole may inhibit the metabolism of drugs metabolized by CYP3A4 and the transport of drugs by P-glycoprotein, which may lead to increased plasma concentrations of these drugs and/or their metabolites. Such increased plasma concentrations may lead to increased or prolonged therapeutic effects and adverse reactions. Concomitant use of itraconazole and drugs metabolized by CYP3A4 that prolong the QT interval is contraindicated, as this may lead to ventricular tachyarrhythmias, including cases of ventricular fibrillation with fatal outcome. After discontinuation of treatment, itraconazole concentrations decrease to levels that are almost undetectable in plasma within 7 to 14 days, depending on the dose and duration of treatment. In patients with cirrhosis or concomitant use of CYP3A4 inhibitors, the drug should be discontinued gradually, especially for drugs whose metabolism is affected by itraconazole.

Concomitant medications are grouped into the following categories:

Contraindicated: under no circumstances should it be used simultaneously with or within 2 weeks of the end of treatment with itraconazole.

Not recommended: The use of these drugs concomitantly and within 2 weeks after discontinuation of itraconazole treatment should be avoided unless the benefit of treatment outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be carefully monitored for signs or symptoms of increased or prolonged pharmacological effects of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor the level of itraconazole plasma concentrations.

Use with caution: Close monitoring is recommended in case of concomitant use with itraconazole. Such patients should be carefully observed for symptoms of increased or prolonged pharmacological effect of itraconazole and, if necessary, the dose of itraconazole should be reduced. It is recommended to monitor the concentration of itraconazole in the blood plasma.

Examples of drugs whose concentrations increase when used concomitantly with itraconazole and recommendations for use

(a) See also “Drugs that decrease itraconazole plasma concentrations.”

(b) See also “Drugs that increase itraconazole plasma concentrations.”

Drugs whose concentration is reduced by itraconazole.

Concomitant use of itraconazole with meloxicam reduces the concentration of the latter. Meloxicam should be prescribed with caution when used concomitantly with itraconazole and therapeutic and side effects should be monitored. It is recommended to adjust the dose of meloxicam.

Children.

Drug interaction studies have only been conducted in adults.

Application features

Cross-hypersensitivity.

There is no evidence of cross-sensitivity between itraconazole and other azole antifungals. Caution should be exercised when prescribing itraconazole to patients with hypersensitivity to other azoles.

Effect on the heart.

In studies with intravenous itraconazole, a transient, asymptomatic decrease in left ventricular ejection fraction was observed; it recovered before the next infusion. The clinical significance of these findings for oral formulations is unknown.

Itraconazole is known to have a negative inotropic effect, and cases of congestive heart failure have been reported in association with its use. Among spontaneous reports, the incidence of congestive heart failure was higher at a total daily dose of 400 mg per day than at lower daily doses. Therefore, the risk of heart failure may increase with the total daily dose of itraconazole.

The drug should not be used in patients with congestive heart failure or a history of it, except in cases where the expected benefit significantly outweighs the potential risk. When assessing the individual benefit/risk ratio, factors such as the severity of the diagnosis, the dosage regimen and duration of treatment (total daily dose), as well as individual risk factors for the development of congestive heart failure should be taken into account. These risk factors include the presence of heart disease, such as ischemic heart disease or valvular disease; severe lung disease, in particular chronic obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the symptoms of congestive heart failure, treatment should be carried out with caution and symptoms of congestive heart failure should be monitored. If these symptoms appear during the course of treatment, the drug should be discontinued.

Calcium channel blockers may have a negative inotropic effect, which may potentiate the same effect of itraconazole. Itraconazole may also inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when itraconazole and calcium channel blockers are used simultaneously due to an increased risk of congestive heart failure (see section "Interaction with other medicinal products and other forms of interaction").

Effect on the liver.

Severe hepatotoxicity, including fatal acute liver failure, has been reported very rarely with itraconazole. Most of these cases occurred in patients with a history of liver disease who were being treated for systemic indications, had other serious illnesses and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases occurred within the first month of treatment, including the first week. Therefore, it is advisable to monitor liver function in patients taking itraconazole. Patients should be advised to seek immediate medical attention if symptoms of hepatitis occur, such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed.

Data on the use of oral forms of itraconazole in patients with hepatic impairment are limited. This drug should be used with caution in this category of patients. Close monitoring of patients with hepatic impairment who are taking itraconazole is recommended. When deciding on treatment with other drugs that are metabolized by CYP3A4, it is recommended to take into account the prolonged half-life of itraconazole, which was observed in clinical studies in patients with cirrhosis who were given single doses of itraconazole tablets.

In patients with elevated liver enzymes, active liver disease, or hepatotoxicity from other medications, treatment should only be initiated if the expected benefit outweighs the risk of liver damage. In such cases, liver function should be monitored.

With reduced gastric acidity, the absorption of itraconazole from tablets is impaired. Patients who are taking antacids (such as aluminum hydroxide) simultaneously with itraconazole should observe at least a two-hour interval between taking these drugs. Patients with achlorhydria, such as AIDS patients or those taking H2 blockers or proton pump inhibitors, are recommended to take itraconazole with cola-type drinks (see section "Interaction with other medicinal products and other types of interactions"). Antifungal activity should be monitored and the dose of itraconazole should be increased if necessary (see section "Interaction with other medicinal products and other types of interactions").

Elderly patients.

Clinical data on the use of itraconazole in elderly patients are limited. The drug should not be used in elderly patients unless the benefits outweigh the potential risks.

Liver dysfunction.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when administering the drug to these patients.

Kidney dysfunction.

Data on the use of oral itraconazole in patients with renal impairment are limited. Caution should be exercised when administering the drug to this category of patients. The bioavailability of oral itraconazole may be reduced in patients with renal impairment. In such cases, dose adjustment should be considered.

Hearing loss.

Cases of temporary or permanent hearing loss have been reported in patients taking itraconazole. In some cases, hearing loss occurred in the context of concomitant use with quinidine, which is contraindicated (see section 4.5). Hearing usually recovers after discontinuation of itraconazole therapy, but in some patients, hearing loss is irreversible.

Patients with immunodeficiency.

In some patients with immunodeficiency (e.g. patients with neutropenia, AIDS or organ transplants), the oral bioavailability of itraconazole may be reduced.

Patients with systemic fungal infections that are immediately life-threatening.

Due to its pharmacokinetic properties (see section 5.2), itraconazole tablets are not recommended for the primary treatment of emergencies caused by systemic fungal infections.

Patients with AIDS.

For patients with AIDS who have been treated for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (meningeal or non-meningeal) and who are at risk of relapse, the physician should assess the need for maintenance treatment.

Neuropathy.

If neuropathy occurs associated with the use of itraconazole, the drug should be discontinued.

Cross-resistance.

If, in the case of systemic candidiasis, it is suspected that the Candida species causing the disease are resistant to fluconazole, it cannot be assumed that they will be susceptible to itraconazole. Therefore, susceptibility testing should be performed before starting treatment with itraconazole.

Interaction potential.

Concomitant use of itraconazole and certain medicinal products may result in altered efficacy of itraconazole and/or the concomitant medicinal product, life-threatening adverse reactions and/or sudden death. Medicinal products that are contraindicated, not recommended or should be used with caution with itraconazole are listed in the section "Interaction with other medicinal products and other forms of interaction".

Excipients.

This medicine contains sugar and lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of the drug on the reaction rate when driving vehicles or operating other mechanisms have not been conducted. It should be borne in mind that side effects such as dizziness, visual disturbances and hearing loss may occur (see section "Adverse reactions"), which may lead to negative consequences when driving vehicles or operating other mechanisms.

Use during pregnancy or breastfeeding

Pregnancy.

Itraconazole should not be administered to pregnant women except in life-threatening conditions when the potential benefit to the pregnant woman outweighs the risk of adverse effects on the fetus.

In animal studies, itraconazole has shown reproductive toxicity.

Women of reproductive age.

Women of reproductive age taking itraconazole should use reliable contraception throughout the course of treatment until the first menstrual period after its completion.

Breastfeeding period.

Small amounts of itraconazole are excreted in breast milk. Therefore, during breastfeeding, the potential risk to the child should be weighed against the expected benefit of treatment with the drug for the mother. If necessary, breastfeeding should be discontinued.

Method of administration and doses

The tablets should be taken orally immediately after a meal to ensure maximum absorption of the drug. The tablets should be swallowed whole.

Adult treatment regimens for each indication:

Indications for use

The duration of treatment for systemic fungal infections should be adjusted depending on the mycological and clinical response to therapy:

Indications for use

Supportive therapy (see section "Special instructions").

(1) The duration of treatment should be adjusted according to clinical response. Impaired absorption in patients with AIDS and neutropenia may result in low blood concentrations of itraconazole and reduced efficacy. In such cases, it is recommended to monitor itraconazole blood levels and, if necessary, increase the dose to 200 mg twice daily.

Elderly patients.

The use of itraconazole in elderly patients is not recommended (see section "Special warnings and precautions for use").

Patients with impaired renal function.

Clinical yes