INSTRUCTION

for medical use of the medicinal product

 

ITRUNGAR

 

 

Composition:

active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

excipients:

pellets contain: hydroxypropyl methylcellulose, corn starch, saccharose;

capsule coat contains:

body: quinoline yellow (E 104), titanium dioxide (E 171), methylparaben (E 218), propylparaben (E 219), sodium lauryl sulfate, purified water, gelatine;

cap: FD&C green No. 3, titanium dioxide (E 171), methylparaben (E 218), propylparaben (E 219), sodium lauryl sulfate, purified water, gelatine.

 

Pharmaceutical form. Capsules.

Basic physical and chemical properties: hard gelatine capsules with a yellow body and green cap or vice versa; capsule contents – white to grey pellets.

 

Pharmacotherapeutic group. Antifungals for systemic use. Triazole and tetrazole derivatives. Itraconazole. ATC code: J02AC02.

 

Pharmacological properties.
Pharmacodynamics.
Itraconazole is a triazole derivative with a broad spectrum of action. In vitro studies have shown that itraconazole inhibits ergosterol synthesis in fungal cells. Ergosterol is an important component of the fungal cell membrane, inhibition of its synthesis provides the antifungal effect.
When using CLSI (Clinical and Laboratory Standards Institute) methods, interpretive breakpoints for itraconazole have not been established for Candida species and filamentous fungi.
For itraconazole, CLSI breakpoints have been established only for Candida spp. causing superficial mycotic infections (CLSI M27-A2). CLSI breakpoints: susceptible ≤0.125; susceptible dose-dependent 0.25–0.5 and resistant ≥1 μg/mL. Interpretive breakpoints have not been established for filamentous fungi.
EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints for itraconazole have been established for Aspergillus flavus, A. fumigatus, A. nidulans and A. terreus and are as follows: susceptible ≤ 1 mg/L, resistant >1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis and are as follows: susceptible ≤ 0.06 mg/L, resistant > 0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis and are as follows: susceptible ≤ 0.125 mg/L, resistant > 0.125 mg/L. EUCAST interpretive breakpoints have not been established for Candida glabrata, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus niger, as well as for interspecies breakpoints for Candida and Aspergillus.
EUCAST breakpoints for itraconazole and Candida species remain to be established.
In vitro studies have shown that itraconazole inhibits the growth of a broad spectrum of fungi pathogenic to humans at concentrations usually ≤1 μg/mL. These include: Candida spp. (including Candida albicans, Candida tropicalis, Candida parapsilosis and Candida dubliniensis), Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp. (including H. capsulatum), Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also exhibited in vitro activity against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and various other yeasts and fungi.
Candida krusei, Candida glabrata and Candida guilliermondii are generally the least susceptible Candida species, and some isolates demonstrate unequivocal resistance to itraconazole in vitro.
The main types of fungi that are 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 usually results from several genetic mutations. The described mechanisms are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 leading to reduced affinity to the target, and/or overexpression of transporters leading to increased efflux. Cross-resistance among medicinal products of the azole class was observed within the Candida species, however resistance to one of the representatives of the class does not necessarily mean the presence of resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Pharmacokinetics.
General pharmacokinetic characteristics.
The peak plasma concentration after oral administration of itraconazole is reached within 2 to 5 hours. Due to non-linear pharmacokinetics, itraconazole accumulates in plasma after repeated use. The steady state is generally achieved within 15 days with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 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 on repeated use. After discontinuation of treatment, the concentration of itraconazole decreases to a level that is almost undetectable in plasma within 7–14 days, depending on the dose and duration of treatment. The mean total plasma clearance of itraconazole after intravenous administration is 278 mL/min. Due to saturable hepatic metabolism, at higher doses the clearance of itraconazole decreases.
Absorption.
Itraconazole is rapidly absorbed after oral administration. The maximum plasma concentration of the unchanged medicinal product after oral administration of capsules is reached within 2–5 hours. The absolute bioavailability of itraconazole is 55 %. The maximum bioavailability when administered orally is observed when the medicinal product is taken immediately after a full meal.
Distribution.
Most of itraconazole binds to plasma proteins (99.8 %), albumin is the main binding component (99.6 % for the hydroxy metabolite). It also has a high affinity for lipids. Only 0.2 % of itraconazole in plasma remains as unbound substance. The apparent volume of distribution of itraconazole in the body is quite significant (> 700 L), from which its wide distribution in tissues can be assumed: concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were 2–3 times higher than plasma concentrations. The accumulation of itraconazole in keratinous tissues, especially in the skin, was 4 times higher than in plasma. The concentration in the cerebrospinal fluid is significantly lower than in plasma, however efficacy against infections localised in the cerebrospinal fluid has been demonstrated.
Biotransformation.
Itraconazole is largely metabolised in the liver with the formation of a large number of metabolites. According to in vitro studies, CYP3A4 is the main enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxyitraconazole, which has antifungal activity in vitro comparable to that of itraconazole. The minimum plasma concentrations of hydroxyitraconazole are approximately 2 times higher than the concentrations of itraconazole.
Elimination.
Approximately 35 % of itraconazole is excreted mainly as inactive metabolites in the urine and about 54 % in the faeces within 1 week after administration of a dose of the oral solution. The renal excretion of itraconazole and the active metabolite hydroxyitraconazole after intravenous administration is less than 1 % of the dose. Following oral administration of a radiolabelled dose, the excretion of unchanged substance in faeces varies from 3 to 18 % of the dose.
Special patient populations.
Hepatic impairment.
Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study with a single dose of 100 mg of itraconazole (1 capsule of 100 mg) was conducted in 6 healthy and 12 patients with cirrhosis. A statistically significant decrease in the mean Cmax (47 %) and a 2-fold increase in the half-life of itraconazole (37±17 vs. 16±5 hours) were found in patients with cirrhosis of the liver compared with healthy volunteers. Although the total exposure of itraconazole calculated on the basis of AUC was comparable in both groups.
No data are available on long-term use of itraconazole in patients with cirrhosis of the liver (see sections "Method of administration and dosage" and "Precautions for use").
Renal impairment.
Data on the use of oral itraconazole in patients with renal impairment are limited. A pharmacokinetic study with a single dose of 200 mg of itraconazole (4 capsules of 50 mg) was conducted in 3 groups of patients with renal impairment (uraemia: n=7, haemodialysis: n=7, continuous ambulatory peritoneal dialysis: n=5). In patients with uraemia with a mean creatinine clearance of 13 mL/min × 1.73 m², the exposure calculated on the basis of AUC was slightly lower compared with the parameters in healthy volunteers. This study did not demonstrate any important effect of haemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0-8h). Plasma concentrations in the time profiles showed significant inter-subject variability in all 3 groups.
After a single intravenous administration of itraconazole, the mean values of the terminal half-life in patients with mild (in this study CrCl 50–79 mL/min), moderate (in this study CrCl 20–49 mL/min) and severe (in this study CrCl ˂20 mL/min) renal impairment were similar to those in healthy volunteers (range of mean values 42–49 hours vs. 48 hours in patients with renal impairment and healthy volunteers, respectively). The total exposure of itraconazole calculated on the basis of AUC was reduced in patients with moderate and severe renal impairment (by 30 % and 40 %, respectively) compared with healthy volunteers.
No data are available on long-term use of itraconazole in patients with renal impairment. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxyitraconazole (see also sections "Method of administration and dosage" and "Precautions for use").
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 using itraconazole capsules, oral solution and solution for intravenous administration. Individual doses using capsules and oral solution varied from 1.5 to 12.5 mg/kg/day, dosing regimen – 1 or 2 times a day. Intravenously, a single dose of 2.5 mg/kg was administered as an infusion or 2.5 mg/kg as infusions 1 or 2 times a day. At the same total daily dose, administration of itraconazole twice daily compared with once daily provided peak and minimum concentrations comparable to once-daily administration in adults. No significant dependence of AUC of itraconazole and total clearance on the patient's age was found, however a weak relationship was noted between the patient's age, volume of distribution, Cmax and the terminal elimination rate of itraconazole. Apparent clearance and volume of distribution probably depended on the patient's body weight.
Preclinical safety data.
Itraconazole.
Acute oral toxicity studies of itraconazole in mice, rats, guinea pigs and dogs indicate a wide margin of safety (4–16 times higher than the maximum recommended human dose (MRHD) of 400 mg/day when converted to mg/m²/day).
Itraconazole is not a primary carcinogen in rats up to 13 mg/kg/day (males) and 52 mg/kg/day (females), or in mice up to 80 mg/kg/day (1 time higher than the MRHD when converted to mg/m²/day).
Preclinical data on itraconazole revealed no signs of genotoxicity, primary carcinogenicity or impaired fertility. At high doses of 40 and 80 mg/kg/day in rats (1–2 times higher than the MRHD when converted to mg/m²/day), effects were observed in the adrenal cortex, liver and mononuclear phagocyte system, but they appear to be of low relevance to the proposed clinical use. Itraconazole at high doses was found to cause a dose-dependent increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice. A general decrease in bone mineral density was observed in young dogs after prolonged administration of itraconazole (toxicity was not observed up to 20 mg/kg/day (2 times higher than the MRHD when converted to mg/m²/day)), and in rats a decrease in bone plate activity, thinning of the compact zone of large bones and increased bone fragility were observed.
Reproductive toxicology.
Itraconazole was found to cause a dose-dependent increase in maternal toxicity, embryotoxicity and teratogenicity in rats at doses of 40 and 160 mg/kg/day (1–4 times higher than the MRHD when converted to mg/m²/day) and in mice at doses of 80 and 160 mg/kg/day (1, 2 and 28 times higher than the MRHD when converted to mg/m²/day). In rats, teratogenicity manifested as significant skeletal defects; in mice – as encephalocele and macroglossia. No teratogenic effects were detected in rabbits at a dose up to 80 mg/kg/day (4 times higher than the MRHD when converted to mg/m²/day).

 

Clinical particulars
Indications

• - Vulvovaginal candidiasis;
• - pityriasis versicolor;
• - dermatophytoses caused by itraconazole-sensitive pathogens (Trichophyton, Microsporum spp., Epidermophyton floccosum), for example, tinea pedis, tinea cruris, tinea corporis, tinea manuum;
• - oropharyngeal candidiasis;
• - onychomycoses caused by dermatophytes and/or yeasts;
• - histoplasmosis;
• - systemic mycoses (in cases where systemic first-line antifungal therapy is inappropriate or ineffective, which may be due to the underlying pathology, insensitivity of the pathogen or toxicity of the medicinal product):
• - treatment of aspergillosis and candidiasis;
• - treatment of cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with cryptococcosis of the central nervous system;
• - maintenance therapy of talaromycosis (formerly penicilliosis) and histoplasmosis only in patients with AIDS;
• - maintenance therapy of cryptococcal meningitis only in patients with AIDS, when standard therapy is considered inappropriate.

Itrungar is also prescribed for the prevention of fungal infection in patients with weakened immunity and severe neutropenia in cases where standard therapy is inappropriate.

 

Contraindications.
The medicinal product is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.
Concomitant use of itraconazole capsules and CYP3A4 substrates is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Precautions for use"). These include:

Analgesics; anaesthetics
Ergot alkaloids (for example, dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Antibacterials for systemic use; antimycobacterial agents; antifungals for systemic use
Isavuconazole
Anthelmintics; antiprotozoals
Halofantrine
Antihistamines for systemic use
Astemizole	Mizolastine	Terfenadine
Antineoplastic agents
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukaemia during the phase of initiation of dosing / titration / dose escalation of venetoclax)
Antiplatelet agents
Dabigatran	Ticagrelor
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensive agents; beta-blockers; calcium channel blockers; agents for the treatment of cardiac diseases; diuretics)
Aliskiren	Dronedarone	Nisoldipine
Bepridil	Eplerenone	Quinidine
Disopyramide	Ivabradine	РанRanolazineолазин
Dofetilide	Lercanidipine	Sildenafil (pulmonary hypertension)
Gastrointestinal agents, including antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride	Domperidone	Naloxegol
Medicinal products that regulate lipid levels
Lovastatin	Lomitapide	Simvastatin
Psychoanaleptics; psycholeptics (for example, antipsychotic agents, anxiolytic agents and hypnotics)
Lurasidone	Pimozide	Sertindole
Midazolam (oral)	Quetiapine	Triazolam
Medicinal products that affect the urinary system
Avanafil	Darifenacin	Solifenacin (in patients with severe renal impairment or moderate and severe hepatic impairment)
Dapoxetine	Fesoterodine (in patients with moderate or severe renal or hepatic impairment)	Vardenafil (in patients aged 75 years and older)
Other medicinal products and substances
Colchicine (in patients with impaired renal or hepatic function)	Eliglustat (in patients who are poor metabolizers of CYP2D6 (PM), intermediate metabolizers (IM) of CYP2D6 or extensive metabolizers (EM) who take a strong or moderate CYP2D6 inhibitor)

 

An increase in the plasma concentrations of these medicinal products caused by concomitant use with itraconazole may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur. For example, an increase in the plasma concentrations of some of these medicinal products may lead to prolongation of the QT interval and ventricular tachyarrhythmias, including cases of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are given in the section "Interaction with other medicinal products and other forms of interaction".
Itraconazole capsules should not be used in patients with ventricular dysfunction, such as congestive heart failure, or congestive heart failure in the anamnesis, except for the treatment of life-threatening infections or other serious infections (see section "Precautions for use").
The medicinal product should not be used during pregnancy, except for the treatment of conditions that threaten the life of the pregnant woman (see section "Pregnancy and lactation").
Women of reproductive age who take itraconazole capsules must use contraceptive measures. Effective contraception should be continued until the onset of menstruation after the end of therapy with the medicinal product.

 

Interaction with other medicinal products and other forms of interaction.
Itraconazole is predominantly metabolised by cytochrome CYP3A4. Other medicinal products that are metabolised by this pathway or modify the activity of CYP3A4 may affect the pharmacokinetics of itraconazole. Itraconazole is a potent inhibitor of CYP3A4, an inhibitor of P-glycoprotein and an inhibitor of breast cancer resistance protein (BCRP).
Itraconazole may alter the pharmacokinetics of other substances that share a common metabolic pathway or protein transport pathway.
Examples of medicinal products that may affect the plasma concentration of itraconazole are given by classes of medicinal products in Table 1 below.
Examples of medicinal products whose plasma concentration may be affected by itraconazole are given in Table 2 below. Due to the large number of interactions, potential changes in the safety or efficacy of the interacting medicinal products are not taken into account. For additional information, refer to the respective instruction for medical use of the interacting medicinal product.
Combinations of itraconazole with the medicinal products described in Tables 1 and 2 are classified as contraindicated, not recommended or such that they should be used with caution with itraconazole, taking into account the degree of increase in concentration and the safety profile of the interacting medicinal product (see also sections "Contraindications" and "Precautions for use" for additional information). The interaction potential of the listed medicinal products was evaluated on the basis of data from pharmacokinetic studies of the use of itraconazole or other strong CYP3A4 inhibitors (for example, ketoconazole) in humans and/or in vitro data:

• - "Contraindicated": under no circumstances should the medicinal product be used simultaneously with itraconazole and for two weeks after discontinuation of itraconazole treatment.
• - "Not recommended": the use of these medicinal products simultaneously and within 2 weeks after discontinuation of itraconazole treatment should be avoided, except in cases where the benefit of treatment outweighs the possible risk of adverse reactions. If simultaneous use cannot be avoided, clinical monitoring of signs or symptoms of increased or prolonged effects or adverse effects of the medicinal product administered simultaneously is recommended, and its dose should be reduced or the administration discontinued, if necessary. If necessary, it is recommended to measure the plasma concentration of the medicinal product administered simultaneously.
• - "Use with caution": careful monitoring is recommended during simultaneous use with itraconazole. During concomitant use, it is recommended to carefully monitor patients for signs or symptoms of increased or prolonged effects or adverse effects of the medicinal product, and also to reduce its dose, if necessary. If necessary, it is recommended to measure the plasma concentration of the medicinal product administered simultaneously.

The interactions given in these tables were characterised in studies conducted with the recommended doses of itraconazole. However, the degree of interaction may depend on the dose of itraconazole administered. A stronger interaction may occur when a higher dose is used or with a shorter interval of administration. Extrapolation of the results to other dosing regimens or other medicinal products should be carried out with caution.
After discontinuation of treatment, the concentration of itraconazole in plasma decreases to almost undetectable within 7–14 days, depending on the dose and duration of treatment. In patients with cirrhosis of the liver or in patients who simultaneously use CYP3A4 inhibitors, the decrease in plasma concentration may be more gradual. This is especially important when starting therapy with medicinal products whose metabolism is impaired by itraconazole (see section "Pharmacokinetics").

Table 1.

Medicinal products that may affect the concentration of itraconazole in plasma, given by classes of medicinal products

Medicinal products (oral single dose, unless otherwise specified) within the class	Expected/potential impact on itraconazole levels: ↑ increase ↔ no changes ↓ decrease	Clinical comment (additionally see the information above, as well as sections "Contraindications" and "Precautions for use")
Antibacterials for systemic use; antimycobacterial agents
Isoniazid	Although isoniazid has not been studied directly, it probably decreases the concentration of itraconazole	Not recommended
Rifampicin orally 600 mg once daily	Itraconazole AUC ↓	Not recommended
Rifabutin orally 300 mg once daily	Itraconazole Cmax ↓ 71 %, AUC ↓ 74 %	Not recommended
Ciprofloxacin orally 500 mg twice daily	Itraconazole Cmax ↑ 53 %, AUC ↑ 82 %	Use with caution
Erythromycin 1 g	Itraconazole Cmax ↑ 44 %, AUC ↑ 36 %	Use with caution
Clarithromycin orally 500 mg twice daily	Itraconazole Cmax ↑ 90 %, AUC ↑ 92 %	Use with caution
Antiepileptic agents
Carbamazepine, phenobarbital	Although these medicinal products have not been studied directly, they probably decrease the concentration of itraconazole	Not recommended
Phenytoin orally 300 mg once daily	Itraconazole Cmax ↓ 83 %, AUC ↓ 93 % Hydroxyitraconazole Cmax ↓ 84 %, AUC ↓ 95 %	Not recommended
Antineoplastic agents
Idelalisib	Although idelalisib has not been studied directly, it will probably increase the concentration of itraconazole	Use with caution
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Although these medicinal products have not been studied directly, they are expected to increase the concentration of itraconazole	Contraindicated
Efavirenz 600 mg	Itraconazole Cmax ↓ 37 %, AUC ↓ 39 % Hydroxyitraconazole Cmax ↓ 35 %, AUC ↓ 37 %	Not recommended
Nevirapine orally 200 mg once daily	Itraconazole Cmax ↓ 38 %, AUC ↓ 62 %	Not recommended
Cobicistat, darunavir (boosted), elvitegravir (boosted with ritonavir), fosamprenavir (boosted with ritonavir), ritonavir, saquinavir (boosted with ritonavir)	Although these medicinal products have not been studied directly, they are expected to increase the concentration of itraconazole	Use with caution
Indinavir orally 800 mg 3 times a day	Itraconazole concentration ↑	Use with caution
Calcium channel blockers
Diltiazem	Although diltiazem has not been studied directly, it probably increases the concentration of itraconazole	Use with caution
Medicinal products for the treatment of disorders associated with increased or decreased acidity
Antacids (aluminium, calcium, magnesium or sodium bicarbonate), H2-receptor antagonists (for example, cimetidine, ranitidine), proton pump inhibitors (for example, lansoprazole, omeprazole, rabeprazole)	Itraconazole Cmax ↓, AUC ↓	Use with caution
Agents affecting the respiratory system
Lumacaftor/ivacaftor orally 200/250 mg twice daily	Itraconazole concentration ↓	Not recommended
Other
St. John's wort (Hypericum perforatum)	Although St. John's wort has not been studied directly, it probably decreases the concentration of itraconazole	Not recommended

Table 2.

Examples of medicinal products whose plasma concentration may be affected by itraconazole, given by classes of medicinal products

Medicinal products (oral single dose, unless otherwise specified) within the class	Expected/potential impact on the levels of the medicinal products: ↑ increase ↔ no changes ↓ decrease	Clinical comment (additionally see the information above, as well as sections "Contraindications" and "Precautions for use")
Analgesics; anaesthetics
Ergot alkaloids (for example, dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Eletriptan, fentanyl	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Not recommended
Alfentanil, buprenorphine (intravenous [IV] and sublingual), cannabinoids, methadone, sufentanil	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Oxycodone orally 10 mg	Oxycodone orally Cmax ↑ 45 %, AUC ↑ 2.4 times	Use with caution
Oxycodone IV 0.1 mg/kg	Oxycodone IV AUC ↑ 51 %	Use with caution
Antibacterials for systemic use; antimycobacterial agents; antifungals for systemic use
Isavuconazole	Although itraconazole has not been studied directly, it probably increases the concentration of isavuconazole	Contraindicated
Bedaquiline	Although itraconazole has not been studied directly, it probably increases the concentration of bedaquiline	Not recommended
Rifabutin orally 300 mg once daily	Rifabutin concentration ↑ (degree unknown)	Not recommended
Clarithromycin orally 500 mg twice daily	Clarithromycin concentration ↑	Use with caution
Delamanid	Although itraconazole has not been studied directly, it probably increases the concentration of delamanid	Use with caution
Antiepileptic agents
Carbamazepine	Although itraconazole has not been studied directly, it probably increases the concentration of carbamazepine	Not recommended
Anti-inflammatory and antirheumatic agents
Meloxicam 15 mg	Meloxicam Cmax ↓ 64 %, AUC ↓ 37 %	Use with caution
Anthelmintics; antiprotozoals
Halofantrine	Although itraconazole has not been studied directly, it probably increases the concentration of halofantrine	Contraindicated
Artemether-lumefantrine, praziquantel	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Quinine 300 mg	Quinine Cmax ↔, AUC ↑ 96 %	Use with caution
Antihistamines for systemic use
Astemizole, mizolastine, terfenadine	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Ebastine 20 mg	Ebastine Cmax ↑ 2.5 times, AUC ↑ 6.2 times Carebastine Cmax ↔, AUC ↑ 3.1 times	Not recommended
Bilastine, rupatadine	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Antineoplastic agents
Irinotecan	Although itraconazole has not been studied directly, it probably increases the concentration of irinotecan and its active metabolite	Contraindicated
Mobocertinib	Mobocertinib: ↑ Cmax 3.8 times, ↑ AUC 8.4 times	Contraindicated
Venetoclax	Although itraconazole has not been studied directly, it probably increases the concentration of venetoclax	Contraindicated in patients with chronic lymphocytic leukaemia during the phase of initiation of treatment / titration / dose escalation of venetoclax. Otherwise, not recommended unless the benefits outweigh the risks. Refer to the instruction for medical use of venetoclax.
Axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, crizotinib, dabrafenib, dasatinib, docetaxel, everolimus, glasdegib, ibrutinib, lapatinib, nilotinib, pazopanib, regorafenib, sunitinib, temsirolimus, trabectedin, trastuzumab emtansine, vinca alkaloids (for example, vinflunine, vinorelbine)	Although itraconazole has not been studied directly, it is probable that it will increase the concentration of these medicinal products, with the exception of cabazitaxel and regorafenib. There are no statistically significant changes in the exposure of cabazitaxel, but a large variability of results is observed. The AUC of regorafenib is expected to decrease (according to the assessment of the active part)	Not recommended
Cobimetinib 10 mg	Cobimetinib Cmax ↑ 3.2 times, AUC ↑ 6.7 times	Not recommended
Entrectinib	Entrectinib Cmax ↑73 %, AUC ↑ 6.0 times	Not recommended
Olaparib 100 mg	Olaparib Cmax ↑ 40 %, AUC ↑ 2.7 times	Not recommended
Talazoparib	Talazoparib Cmax ↑ 40 %, AUC ↑ 56 %	Not recommended
Alitretinoin (oral), bortezomib, brentuximab vedotin, erlotinib, idelalisib, imatinib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, tretinoin (oral)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Busulfan 1 mg/kg every 6 hours	Busulfan Cmax ↑, AUC ↑	Use with caution
Gefitinib 250 mg	Gefitinib 250 mg Cmax ↑, AUC ↑ 78 %	Use with caution
Pemigatinib	Pemigatinib Cmax ↑ 17 %, AUC ↑ 91 %	Use with caution
Antiplatelet agents
Dabigatran, ticagrelor	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Not recommended
Cilostazol, coumarins (for example, warfarin)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase the concentration of paritaprevir	Contraindicated
Elbasvir/grazoprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Not recommended
Cobicistat, elvitegravir (boosted with ritonavir), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Indinavir orally 800 mg 3 times a day	Indinavir Cmax ↔, AUC ↑	Use with caution
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensive agents; beta-blockers; calcium channel blockers; cardiac therapy; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, ivabradine, lercanidipine, nisoldipine, ranolazine, sildenafil (pulmonary hypertension)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Finerenone	Although itraconazole has not been studied directly, it probably increases the concentration of this medicinal product	Contraindicated
Aliskiren 150 mg	Aliskiren Cmax ↑ 5.8 times, AUC ↑ 6.5 times	Contraindicated
Quinidine 100 mg	Quinidine Cmax ↑ 59 %, AUC ↑ 2.4 times	Contraindicated
Felodipine 5 mg	Felodipine Cmax ↑ 7.8 times, AUC ↑ 6.3 times	Not recommended
Riociguat, tadalafil (pulmonary hypertension)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (for example, amlodipine, isradipine, nifedipine, nimodipine), verapamil	Although itraconazole has not been studied directly, it probably increases the concentration of bosentan	Use with caution
Digoxin 0.5 mg	Digoxin Cmax ↑ 34 %, AUC ↑ 68 %	Use with caution
Nadolol 30 mg	Nadolol Cmax ↑ 4.7 times, AUC ↑ 2.2 times	Use with caution
Corticosteroids for systemic use; medicinal products for the treatment of obstructive airway diseases
Ciclesonide, salmeterol	Although itraconazole has not been studied directly, it probably increases the concentration of salmeterol and the active metabolite of ciclesonide	Not recommended
Budesonide inhalation 1 mg once	Budesonide inhalation Cmax ↑ 65 %, AUC ↑ 4.2 times Budesonide (other dosage forms) concentration ↑	Use with caution
Dexamethasone IV 5 mg Dexamethasone orally 4.5 mg	Dexamethasone IV: Cmax ↔, AUC ↑ 3.3 times Dexamethasone orally: Cmax ↑ 69 %, AUC ↑ 3.7 times	Use with caution
Fluticasone inhalation 1 mg twice daily	Concentration of fluticasone inhalation ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone orally Cmax ↑ 92 %, AUC ↑ 3.9 times Methylprednisolone IV AUC ↑ 2.6 times	Use with caution
Fluticasone nasal	Although itraconazole has not been studied directly, it probably increases the concentration of fluticasone administered intranasally	Use with caution
Medicinal products used in diabetes mellitus
Repaglinide 0.25 mg	Repaglinide Cmax ↑ 47 %, AUC ↑ 41 %	Use with caution
Saxagliptin	Although itraconazole has not been studied directly, it probably increases the concentration of saxagliptin	Use with caution
Gastrointestinal agents, including antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride, naloxegol	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Domperidone 20 mg	Domperidone Cmax ↑ 2.7 times, AUC ↑ 3.2 times	Contraindicated
Aprepitant, loperamide, netupitant	Although itraconazole has not been studied directly, it probably increases the concentration of aprepitant Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Although itraconazole has not been studied directly, it probably increases the concentration of sirolimus	Not recommended
Cyclosporine, tacrolimus	Although itraconazole has not been studied directly, it probably increases the concentration of cyclosporine	Use with caution
Tacrolimus IV 0.03 mg/kg once daily	Concentration of tacrolimus IV ↑	Use with caution
Voclosporin	Although itraconazole has not been studied directly, it probably increases the concentration of voclosporin	Contraindicated
Medicinal products that regulate lipid levels
Lomitapide	Although itraconazole has not been studied directly, it probably increases the concentration of lomitapide	Contraindicated
Lovastatin 40 mg	Lovastatin Cmax ↑ 14.5 – >20 times, AUC ↑ > 14.8 – >20 times Lovastatin acid Cmax ↑ 11.5–13 times, AUC ↑ 15.4–20 times	Contraindicated
Simvastatin 40 mg	Simvastatin acid Cmax ↑ 17 times, AUC ↑ 19 times	Contraindicated
Atorvastatin	Atorvastatin acid Cmax ↑ up to 2.5 times, AUC ↑ from 40 % to 3 times	Not recommended
Psychoanaleptics; psycholeptics (for example, antipsychotic agents, anxiolytic agents and hypnotics)
Lurasidone, pimozide, quetiapine, sertindole	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Midazolam (oral) 7.5 mg	Midazolam (oral) Cmax ↑ 2.5–3.4 times, AUC ↑ 6.6–10.8 times	Contraindicated
Triazolam 0.25 mg	Triazolam Cmax ↑, AUC ↑	Contraindicated
Alprazolam 0.8 mg	Alprazolam Cmax ↔, AUC ↑ 2.8 times	Use with caution
Aripiprazole 3 mg	Aripiprazole Cmax ↑ 19 %, AUC ↑ 48%	Use with caution
Brotizolam 0.5 mg	Brotizolam Cmax ↔, AUC ↑ 2.6 times	Use with caution
Buspirone 10 mg	Buspirone Cmax ↑ 13.4 times, AUC ↑ 19.2 times	Use with caution
Midazolam (IV) 7.5 mg	Concentration of midazolam (IV) 7.5 mg: ↑ Although itraconazole has not been studied directly, it probably increases the concentration of midazolam for oromucosal administration	Use with caution
Risperidone 2–8 mg/day	Concentration of risperidone and active metabolite ↑	Use with caution
Zopiclone 7.5 mg	Zopiclone Cmax ↑ 30 %, AUC ↑ 70 %	Use with caution
Cariprazine, galantamine, haloperidol, reboxetine, venlafaxine	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Agents affecting the respiratory system
Lumacaftor/ivacaftor orally 200/250 mg twice daily	Ivacaftor Cmax ↑ 3.6 times, AUC ↑ 4.3 times Lumacaftor Cmax ↔, AUC ↔	Not recommended
Ivacaftor	Although itraconazole has not been studied directly, it probably increases the concentration of ivacaftor	Use with caution
Sex hormones and modulators of the reproductive system; other gynaecological agents
Cabergoline, dienogest, ulipristal	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Medicinal products that affect the urinary system
Avanafil, dapoxetine, darifenacin	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Contraindicated
Fesoterodine	Although itraconazole has not been studied directly, it probably increases the concentration of active metabolites, 5-hydroxymethyltolterodine	Moderate or severe impairment of renal or hepatic function: contraindicated. Mild impairment of renal or hepatic function: simultaneous use should be avoided. Normal function of kidneys and liver: use with caution with a maximum dose of fesoterodine 4 mg
Solifenacin	Although itraconazole has not been studied directly, it probably increases the concentration of solifenacin	Severe impairment of renal function: contraindicated. Moderate or severe impairment of hepatic function: contraindicated. Use with caution in all other patients with a maximum dose of solifenacin 5 mg.
Vardenafil	Although itraconazole has not been studied directly, it probably increases the concentration of vardenafil	Contraindicated in patients aged 75 years and older; not recommended for other patients.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Although itraconazole has not been studied directly, it probably increases the concentration of these medicinal products	Use with caution
Oxybutynin 5 mg	Oxybutynin Cmax ↑ 2 times, AUC ↑ 2 times Cmax of N-desethyloxybutynin ↔, AUC ↔ Although itraconazole has not been studied directly, it probably increases the concentration of oxybutynin after transdermal administration	Use with caution
Other medicinal products and substances
Colchicine	Although itraconazole has not been studied directly, it probably increases the concentration of colchicine	Contraindicated in patients with impaired renal or hepatic function. Not recommended for other patients.
Eliglustat	Although itraconazole has not been studied directly, it probably increases the concentration of eliglustat	Contraindicated for poor metabolizers of CYP2D6 (PM). Contraindicated for intermediate metabolizers (IM) or extensive metabolizers (EM) who take a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IM and EM. For CYP2D6 EM with mild hepatic impairment, the possibility of using eliglustat at a dose of 84 mg/day should be considered.
Cinacalcet	Although itraconazole has not been studied directly, it probably increases the concentration of cinacalcet	Use with caution

 

Precautions for use.
Cross-hypersensitivity
There are no data on cross-hypersensitivity between itraconazole and other azole antifungal agents. Itraconazole capsules should be prescribed with caution in patients with hypersensitivity to other azoles.
Effects on the heart
It has been reported that in studies with the use of itraconazole for intravenous administration in healthy volunteers, a transient asymptomatic decrease in the left ventricular ejection fraction was observed, it was restored before the next infusion. The clinical significance of these data for oral forms has not been clarified.
It is known that itraconazole exhibits a negative inotropic effect. Cases of congestive heart failure associated with the use of itraconazole have been reported. According to spontaneous reports, the incidence of congestive heart failure was higher at a total daily dose of 400 mg per day than with a lower daily dose, therefore the risk of heart failure may increase with an increase in the total daily dose of itraconazole.
The medicinal product should not be used in patients with congestive heart failure now or in the anamnesis, except in cases where the expected benefit significantly exceeds the potential risk. In an individual assessment of the benefit/risk ratio, factors such as the severity of the diagnosis, the dosing regimen (for example, the total daily dose) and individual risk factors for the occurrence of congestive heart failure should be taken into account. These risk factors include the presence of cardiac diseases, such as ischaemic heart disease or valvular defects; severe lung diseases, in particular chronic obstructive pulmonary disease; renal failure or other diseases accompanied by oedema. Such patients should be informed about the signs and symptoms of congestive heart failure, and treatment should be carried out with caution and the manifestations and symptoms of congestive heart failure should be monitored during treatment. If these manifestations and symptoms appear during the course of treatment, the use of the medicinal product must be discontinued.
Calcium channel blockers may have a negative inotropic effect, which may be enhanced by itraconazole. Itraconazole may also inhibit the metabolism of calcium channel blockers. Therefore, caution should be observed with the simultaneous use of itraconazole and calcium channel blockers due to the increased risk of congestive heart failure (see section "Interaction with other medicinal products and other forms of interaction").
Effects on the liver
With the use of itraconazole capsules, severe hepatotoxicity has been reported very rarely, including some cases of acute hepatic failure with a fatal outcome. For the most part, these cases were observed in patients with liver diseases in the anamnesis, who were treated for systemic indications, had other serious diseases and/or took other hepatotoxic medicinal products. In some patients, there were no obvious risk factors for liver diseases. Some of these cases were observed during the first month of treatment, including the first week. Therefore, it is advisable to monitor liver function in patients who take itraconazole capsules. Patients should be warned about the need to urgently consult a doctor in case of manifestations of signs or symptoms of hepatitis, namely: anorexia, nausea, vomiting, fatigue, abdominal pain or darkening of urine. In the presence of these symptoms, treatment must be immediately discontinued and a liver function test performed.
Limited data are available on the oral use of itraconazole in patients with hepatic impairment. This medicinal product should be used with caution in this category of patients. Careful monitoring of the condition of patients with hepatic impairment who take itraconazole is recommended. When deciding to start treatment with other medicinal products that are metabolised by CYP3A4, it is recommended to take into account the prolonged half-life of itraconazole observed in clinical studies involving patients with cirrhosis of the liver who were administered single doses of itraconazole capsules.
For patients with elevated or abnormal liver enzyme levels, active liver disease or manifestations of hepatotoxicity due to the use of other medicinal products, treatment with itraconazole is categorically not recommended, unless there is a severe or life-threatening situation where the expected benefit exceeds the risk. Monitoring of liver function is recommended in patients with hepatic impairment or patients with a history of hepatic toxicity caused by the action of other medicinal products (see section "Pharmacological properties. Pharmacokinetics. Special patient populations. Hepatic impairment").
Reduced gastric acidity
With reduced gastric acidity, the absorption of itraconazole worsens. For patients with reduced gastric acidity caused by a disease (for example, achlorhydria) or simultaneous use of other medicinal products (for example, to reduce gastric acidity), it is recommended to use the medicinal product with beverages with increased acidity (for example, non-diet cola). Antifungal activity should be monitored and the dose of itraconazole should be increased, if necessary (see section "Interaction with other medicinal products and other forms of interaction").
Children
Clinical data on the use of itraconazole capsules in children are limited. The use of itraconazole capsules in children is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Elderly patients
Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole should not be used in elderly patients unless the benefit of use outweighs the potential risk. In general, it is recommended to select the dose for elderly patients taking into account the greater frequency of decreased function of the liver, kidneys or heart, as well as the presence of concomitant diseases or the use of other medicinal products.
Renal impairment
Data on the use of itraconazole orally in patients with renal impairment are limited. Exposure to itraconazole may be lower in some patients with renal failure. Caution should be exercised when using the medicinal product in this category of patients, and the issue of dose adjustment may also be considered.
Hearing loss
Cases of temporary or permanent hearing loss have been reported in patients who took itraconazole. In some of these cases, hearing loss occurred against the background of simultaneous use with quinidine, which is contraindicated (see section "Interaction with other medicinal products and other forms of interaction"). Hearing usually returns after the end of itraconazole therapy, however in some patients hearing loss is irreversible.
Patients with immunosuppression
In some patients with immunosuppression (for example, patients with neutropenia, AIDS or transplanted organs), the oral bioavailability of itraconazole capsules may be reduced. Impaired absorption in patients with AIDS and neutropenia may lead to low levels of itraconazole in the blood and lack of efficacy. The dose should be adjusted based on the clinical response in these patients (see section "Method of administration and dosage"). Monitoring of therapeutic blood levels may be required.
Patients with systemic fungal infections that directly threaten life
Due to the pharmacokinetic properties (see section "Pharmacokinetics"), itraconazole capsules are not recommended for primary therapy of emergency conditions caused by systemic fungal infections.
Patients with AIDS
The doctor should assess the need for maintenance treatment in patients with AIDS who received treatment for a systemic fungal infection, such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are at risk of relapse.
Neuropathy
If neuropathy associated with the use of itraconazole occurs, treatment should be discontinued.
Cystic fibrosis
In patients with cystic fibrosis, variability in the plasma levels of itraconazole was observed, leading to subtherapeutic concentrations. The risk of subtherapeutic concentrations may be higher in patients under 16 years of age. If the patient does not respond to itraconazole capsules, the possibility of switching to alternative therapy should be considered.
Carbohydrate metabolism disorders
The medicinal product contains sucrose. Patients with rare hereditary conditions of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not use this medicinal product.
Cross-resistance
If, in systemic candidiasis, there is a suspicion that the Candida species causing the disease are resistant to fluconazole, it cannot be stated that they will be sensitive to itraconazole. Therefore, a sensitivity test must be performed before starting treatment with itraconazole.
Interchangeability.
Interchangeable use of itraconazole capsules and oral itraconazole solution is not recommended. This is due to the fact that the exposure of the medicinal product is higher with the use of the oral solution than with capsules, at the same dose of the medicinal product.
Interaction potential
Simultaneous use of itraconazole and certain medicinal products may lead to a change in the effectiveness of itraconazole and/or the medicinal product used simultaneously with it, to the occurrence of adverse reactions that may threaten life, and/or to a sudden fatal outcome. Medicinal products that are contraindicated, that should not be used or that are allowed to be used with caution simultaneously with itraconazole are given in sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

 

Pregnancy and lactation.
Pregnancy
Itraconazole capsules should not be prescribed to pregnant women, except for conditions that threaten life, when the potential benefit to the pregnant woman exceeds the risk of a negative effect on the foetus (see section "Contraindications").
In animal studies, itraconazole showed reproductive toxicity (see section "Pharmacological properties. Preclinical safety data").
Data on the use of itraconazole during pregnancy are limited. During post-marketing use, cases of congenital anomalies were reported, such as malformations of the skeleton, genitourinary tract, cardiovascular system and organs of vision, as well as chromosomal anomalies and multiple malformations. A causal relationship with itraconazole has not been established.
Epidemiological data on the effect of itraconazole on women in the first trimester of pregnancy (mainly in patients who used it for short-term treatment of vulvovaginal candidiasis) did not reveal an increased risk of malformations compared with that in women who did not use medicinal products with a teratogenic effect. In an experiment in rats, it was shown that itraconazole penetrates the placenta.
Women of reproductive age
Women of reproductive age who take itraconazole capsules must use contraceptive measures. Effective contraception should be continued until the onset of menstruation after the end of itraconazole therapy.
Breastfeeding
Very small amounts of itraconazole penetrate into breast milk. Therefore, during breastfeeding, it is necessary to compare the possible risk for the child with the expected benefit of treatment with itraconazole for the mother. In doubtful cases, the woman should stop breastfeeding.

 

Effects on ability to drive vehicles or other mechanisms.
Studies on the effect on the ability to drive vehicles and work with mechanisms have not been conducted. It should be remembered about the possibility of occurrence in some cases of such adverse reactions as dizziness, visual disturbances and hearing loss (see section "Adverse reactions").

 

Method of administration and dosage.
Itrungar capsules should be used orally immediately after meals to ensure maximum absorption of the medicinal product. Capsules should be swallowed whole.

Table 3

Treatment regimens for adults for each indication

Indications for use	Dosage	Duration	Remarks
• Vulvovaginal candidiasis	200 mg twice daily	1 day
• Pityriasis versicolo	200 mg once daily	7 days
• Tinea corporis • Tinea cruris	100 mg once daily	15 days
	200 mg once daily	7 days
• Tinea pedis • Tinea manuum	100 mg once daily	30 days
• Oropharyngeal candidiasis	100 mg once daily	15 days	The dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS due to impaired absorption of the medicinal product in these patients.
• Onychomycosis (lesion of nail plates on the toes, both with and without lesion of the nails on the hands)	200 mg once daily	3 months

 

Optimal clinical and mycological effects are achieved 1–4 weeks after the end of treatment of skin infections, vulvovaginal and oropharyngeal candidiasis and after 6–9 months after completion of treatment of nail plate infection. This is due to the fact that the elimination of itraconazole from the tissues of the skin, nails and mucous membranes occurs more slowly than from blood plasma.
The duration of treatment of systemic fungal lesions should be adjusted depending on the mycological and clinical response to therapy.

Table 4

Systemic mycoses

Indications for use	Dosage¹	Remarks
Aspergillosis	200 mg once daily	Increase of the dose to 200 mg twice daily in case of invasive or disseminated disease
Candidiasis	100–200 mg once daily	Increase of the dose to 200 mg twice daily in case of invasive or disseminated disease
Cryptococcosis (without signs of meningitis)	200 mg once daily
Cryptococcal meningitis	200 mg twice daily
Histoplasmosis	200 mg once daily to 200 mg twice daily
Maintenance therapy of talaromycosis (formerly penicilliosis) and histoplasmosis only in patients with AIDS	200 mg once or twice daily until immune restoration	The duration of treatment should be based on the state of immune restoration.
Maintenance therapy of cryptococcal meningitis only in patients with AIDS	200 mg twice daily until immune restoration	The duration of treatment should be based on the state of immune restoration.
Prevention of fungal infections in patients with immunosuppression with severe neutropenia	200 mg twice daily until immune restoration	Start 1–3 days before or at the beginning of chemotherapy until the disappearance of neutropenia.

¹ The dose and duration of treatment should be adjusted depending on the clinical response (see section "Precautions for use").

 

Special populations
Children.
Clinical data on the use of itraconazole capsules in children are limited. The use of itraconazole capsules in children is not recommended unless it is determined that the potential benefit outweighs the potential risks (see section "Precautions for use").
Elderly patients.
Clinical data on the use of itraconazole capsules in elderly patients are limited. It is recommended to use itraconazole capsules in these patients only when it is determined that the potential benefit outweighs the potential risks. In general, when choosing a dose for an elderly patient, it is recommended to take into account the greater frequency of decreased function of the liver, kidneys or heart, as well as concomitant diseases or other medicinal therapy (see section "Precautions for use").
Patients with renal impairment.
Clinical data on the use of oral forms of itraconazole in patients with renal impairment are limited. The exposure of the medicinal product when administered orally may be reduced in some patients with renal failure. Caution should be exercised when using this medicinal product in such patients and the issue of dose adjustment may be considered.
Patients with hepatic impairment.
Clinical data on the use of oral forms of itraconazole in patients with hepatic impairment are limited. Caution should be exercised when using this medicinal product in such patients (see section "Pharmacological properties. Pharmacokinetics. Special patient populations. Hepatic impairment").

Children.
Clinical data on the use of itraconazole capsules in children are limited. The use of itraconazole capsules in children is not recommended unless it is determined that the potential benefit outweighs the potential risks.

 

Overdose.
Symptoms and signs.
In general, the adverse reactions reported in case of overdose had a similar profile to the adverse reactions that occurred with the use of itraconazole (see section "Adverse reactions").
Treatment.
In case of overdose, supportive measures should be taken. Itraconazole cannot be removed by haemodialysis. There is no specific antidote. According to the latest recommendations for the treatment of overdose, it is recommended to contact a toxicology centre.

 

Adverse reactions.
Brief description of the safety profile.
The most frequent adverse reactions with the use of the medicinal product, which were reported during clinical studies and in spontaneous reports, were headache, abdominal pain and nausea. The most serious adverse reactions were serious allergic reactions, cardiac failure / congestive heart failure / pulmonary oedema, pancreatitis, severe hepatotoxicity (including several cases of acute hepatic failure with a fatal outcome) and severe skin reactions. The frequency of these adverse reactions and other adverse reactions are given below. For additional information on other serious effects, see section "Precautions for use".
List of adverse reactions.
Adverse reactions listed below were reported during open and double-blind clinical trials of itraconazole capsules involving 8499 patients who received itraconazole for the treatment of dermatomycoses or onychomycoses, and from spontaneous reports.
Adverse reactions listed below are grouped by organ systems, within each group by organ systems they are indicated by frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (˂ 1/10000).
Infections and infestations:
Uncommon – sinusitis, upper respiratory tract infections, rhinitis.
Blood and lymphatic system disorders:
Rare – leukopenia.
Immune system disorders:
Uncommon – hypersensitivity*.
Rare – serum sickness, angioedema, anaphylactic reactions.
Endocrine disorders:
Frequency unknown – pseudoaldosteronism.
Metabolism and nutrition disorders:
Rare – hypertriglyceridaemia.
Nervous system disorders:
Common – headache.
Rare – paraesthesia, hypoaesthesia, dysgeusia, tremor.
Eye disorders:
Rare – visual disturbances (including diplopia and blurred vision).
Ear and labyrinth disorders:
Rare – temporary or permanent hearing loss*, tinnitus.
Cardiac disorders:
Rare – congestive heart failure*.
Respiratory, thoracic and mediastinal disorders:
Rare – dyspnoea.
Gastrointestinal disorders:
Common – abdominal pain, nausea.
Uncommon – diarrhoea, vomiting, constipation, dyspepsia, flatulence.
Rare – pancreatitis.
Hepatobiliary disorders:
Uncommon – hepatic function disorder.
Rare – severe hepatotoxicity (including several cases of fulminant hepatic failure with a fatal outcome)*, hyperbilirubinaemia.
Skin and subcutaneous tissue disorders:
Uncommon – urticaria, rash, pruritus.
Rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.
Renal and urinary disorders:
Rare – pollakiuria (frequent urination).
Reproductive system and breast disorders:
Uncommon – menstrual cycle disorders.
Rare – erectile dysfunction.
General disorders and administration site conditions:
Rare – oedema.
Laboratory investigations:
Rare – increase in the level of creatine phosphokinase in the blood.

* See section "Precautions for use".

 

List of individual adverse reactions.
Below are the adverse reactions associated with the use of itraconazole, which were reported during clinical studies of the oral solution and solution for intravenous use, with the exception of inflammation at the injection site, since this adverse reaction is specific only to the solution for intravenous administration.
Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.
Immune system disorders: anaphylactoid reactions.
Metabolism and nutrition disorders: hyperglycaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia.
Psychiatric disorders: confusion.
Nervous system disorders: peripheral neuropathy*, dizziness, somnolence.
Cardiac disorders: cardiac failure, left ventricular failure, tachycardia.
Vascular disorders: arterial hypertension, arterial hypotension.
Respiratory, thoracic and mediastinal disorders: pulmonary oedema, dysphonia, cough.
Gastrointestinal disorders: gastrointestinal disorders.
Hepatobiliary disorders: hepatic failure*, hepatitis, jaundice.
Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia.
Renal and urinary disorders: renal failure, urinary incontinence.
General disorders and administration site conditions: generalized oedema, facial oedema, chest pain, pyrexia, pain, fatigue, chills.
Laboratory investigations: increase in the level of alanine aminotransferase (ALT), increase in the level of aspartate aminotransferase (AST), increase in the level of alkaline phosphatase, increase in the level of lactate dehydrogenase in the blood, increase in the level of urea in the blood, increase in the level of gamma-glutamyltransferase (GGT), increase in the level of hepatic enzymes, deviation from the norm in the results of urine analysis.
Children.
The safety of the medicinal product was studied with the participation of 165 children aged 1 to 17 years who participated in 14 clinical studies (4 double-blind, placebo-controlled studies; 9 open-label studies; 1 study with an open-label phase followed by a double-blind phase). These patients received at least 1 dose of itraconazole capsules for the treatment of fungal infections and provided safety data.
Based on the summarized safety data obtained in these clinical studies, the adverse reactions that were frequently reported in children were: headache (3.0 %), vomiting (3.0 %), abdominal pain (2.4 %), diarrhoea (2.4 %), hepatic function disorders (1.2 %), arterial hypotension (1.2 %), nausea (1.2 %) and urticaria (1.2 %). In general, the profile of adverse reactions in children is similar to that in adults, however the frequency of their occurrence is higher in children.

 

Reporting of suspected adverse reactions
Reporting of adverse reactions after the registration of a medicinal product is of great importance. This enables monitoring of the benefit/risk ratio with the use of this medicinal product. Medical and pharmaceutical workers, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua

 

Shelf life. 2 years.

 

Storage conditions.
Keep out of the reach of children in the original packaging at a temperature not exceeding 25 ºС.

 

Packaging. 4 or 15 capsules in a blister. 1 blister in a carton.

 

Terms of dispensing. On prescription.

 

Date of last update.
24.07.2026