Ezol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESZOL (ESZOL®)

Composition:

Active substance: itraconazole;

1 tablet contains 100 mg of itraconazole;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: capsule-shaped, film-coated pink tablets with the imprint "ITR 100" on one side.

Pharmacotherapeutic group.
Antifungal agents for systemic use. ATC code J02A C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Itraconazole inhibits fungal 14α-demethylase, leading to depletion of ergosterol and disruption of fungal membrane synthesis.

The pharmacokinetic/pharmacodynamic relationship for itraconazole, as with triazoles in general, is not well understood.

Mechanisms of resistance

Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. The following mechanisms have been described:

• overexpression of the ERG11 gene encoding 14α-demethylase (the target enzyme);
• point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole;
• overexpression of efflux transporters, resulting in increased export of itraconazole from fungal cells (i.e., removal of itraconazole from its target site);
• cross-resistance among azole-class drugs, observed across various Candida species. However, resistance to one azole agent does not necessarily imply resistance to other azoles.

Breakpoints

Breakpoints for itraconazole have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), version 10.0, effective from 2020-02-04.

* Minimum inhibitory concentration (MIC).

Currently, there is insufficient evidence to establish clinical breakpoints for Candida glabrata³, C. krusei³, C. guilliermondii³, Cryptococcus neoformans, and for microorganisms not associated with Candida.

Currently, there is also insufficient evidence to establish clinical breakpoints for Aspergillus niger^4,5 and for species not associated with Aspergillus spp.⁵.

1 Azole concentration monitoring is recommended in patients being treated for fungal infections.

2 The technical uncertainty zone (ATU) is 2. Report as R with the following comment: "In certain clinical situations (non-invasive forms of infection), itraconazole may be used provided adequate exposure is ensured."

3 Epidemiological cutoff values (ECOFF) for these species are generally higher than for C. albicans.

4 Epidemiological cutoff values (ECOFF) for these species are usually one two-fold dilution higher than for A. fumigatus.

5 MIC values for A. niger and A. versicolor isolates are generally higher than for A. fumigatus. It is unknown whether this leads to poorer clinical response.

Interpretive breakpoints for itraconazole have not been established for Candida species and filamentous fungi (when using methods for antifungal susceptibility testing of yeasts).

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local resistance data are desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence makes the utility of itraconazole at least questionable for certain types of infections.

Fungal susceptibility to itraconazole in vitro depends on the inoculum size, incubation temperature, fungal growth phase, and culture medium used. For these reasons, the MIC of itraconazole may vary widely. The susceptibility data presented in the table below are based on an MIC₉₀ < 1 mg itraconazole/L. There is no correlation between in vitro susceptibility and clinical efficacy.

1. These microorganisms may be encountered in patients who have returned from traveling outside Europe.

2. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

3. Naturally intermediate susceptibility.

Pharmacokinetics.

General pharmacokinetic characteristics

Maximum plasma concentration (Cmax) after oral administration of itraconazole is reached within 2 to 5 hours. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after repeated dosing. Steady-state concentrations are usually achieved within 15 days, with Cmax values of approximately 0.5 μg/mL, 1.1 μg/mL, and 2.0 μg/mL after administration of 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal half-life of itraconazole ranges from 16 to 28 hours after a single dose and increases to 34–42 hours after multiple doses. After discontinuation of treatment, itraconazole concentrations decrease to nearly undetectable levels in plasma within 7–14 days, depending on the dose and duration of therapy. The mean plasma clearance of itraconazole after intravenous administration is 278 mL/min. Due to saturated hepatic metabolism at higher doses, the clearance of itraconazole decreases.

Absorption

Itraconazole is rapidly absorbed after oral administration. Cmax is reached within 2–5 hours after oral intake. The absolute bioavailability of itraconazole is 55%. Maximum bioavailability following oral administration is observed when a high-calorie meal is consumed immediately after taking the drug.

Absorption of itraconazole in tablet form is reduced in patients with decreased gastric acidity, in patients taking acid-reducing agents (H2-receptor antagonists, proton pump inhibitors), or in patients with achlorhydria due to certain diseases (see sections "Interaction with other medicinal products and other forms of interactions" and "Special precautions for use"). Fasting absorption of itraconazole in these patients increases when Esol tablets are taken with acidic beverages (e.g., non-diet cola). When itraconazole was administered as a single 200 mg dose on an empty stomach with non-diet cola following ranitidine (an H2-receptor antagonist), its absorption was comparable to that observed after itraconazole administration alone (see also section "Interaction with other medicinal products and other forms of interactions"). Exposure to itraconazole is lower when tablets are used compared to the oral solution administered at the same dose (see section "Special precautions for use").

Distribution

The majority of itraconazole is bound to plasma proteins (99.8%), with albumin being the primary binding component (99.6% for the hydroxymetabolite). Itraconazole also has high affinity for fatty tissues. Only 0.2% of itraconazole in blood remains as unbound drug. The apparent volume of distribution of itraconazole is very large (> 700 L), suggesting extensive tissue distribution: concentrations in lungs, kidneys, liver, bones, stomach, spleen, and muscles were 2–3 times higher than in plasma. Accumulation of itraconazole in keratinous tissues, particularly in the skin, was four times higher than in plasma. Concentrations in cerebrospinal fluid are significantly lower than in plasma, yet efficacy against infections localized in cerebrospinal fluid has been demonstrated.

Biotransformation

Itraconazole is extensively metabolized in the liver, producing numerous metabolites. One such metabolite is hydroxyitraconazole, which exhibits antifungal activity comparable to that of itraconazole in vitro. The plasma concentration of hydroxyitraconazole is approximately twice that of itraconazole.

Elimination

Approximately 35% of itraconazole is excreted in urine and about 54% in feces as inactive metabolites within one week after oral administration of the solution dose. Renal excretion of unchanged itraconazole and its active metabolite hydroxyitraconazole accounts for less than 1% of an intravenous dose. Based on orally administered radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18%. Since redistribution of itraconazole from keratinized tissues is minimal, elimination from these tissues is associated with epidermal regeneration. Unlike plasma, concentrations in the skin persist for 2–4 weeks after completion of a 4-week treatment course, and in nail keratin, where itraconazole can be detected as early as one week after initiation of therapy, concentrations remain detectable for at least 6 months after completion of a 3-month treatment period.

Special patient populations

Hepatic impairment

Itraconazole is primarily metabolized in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole was conducted in 6 healthy subjects and 12 patients with liver cirrhosis. In cirrhotic patients, a clinically significant reduction in mean Cmax (by 47%) and a doubling of the elimination half-life (37 ± 17 vs. 16 ± 5 hours) were observed compared to healthy volunteers, although total itraconazole exposure based on the area under the concentration-time curve (AUC) was comparable between the two groups.

No data are available on long-term use of itraconazole in patients with liver cirrhosis.

Renal impairment

Data on the use of oral itraconazole in patients with impaired renal function are limited.

A pharmacokinetic study using a single 200 mg dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n = 7; hemodialysis: n = 7; continuous ambulatory peritoneal dialysis: n = 5). In uremic patients with a mean creatinine clearance of 13 mL/min × 1.73 m², AUC-based concentrations were slightly lower compared to healthy volunteers. The study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0–8h). Plasma concentration profiles showed considerable inter-subject variability in all three groups.

After a single intravenous dose, the mean terminal half-life of itraconazole in patients with mild (defined in this study as CrCl 50–79 mL/min), moderate (defined as CrCl 20–49 mL/min), and severe renal impairment (defined as CrCl < 20 mL/min) was similar to that in healthy volunteers (range: 42–49 hours vs. 48 hours in patients with renal impairment and healthy volunteers, respectively). Total itraconazole exposure, assessed by AUC, was reduced by approximately 30% and 40% in patients with moderate and severe renal impairment, respectively, compared to patients with normal renal function.

No data are available on long-term use of itraconazole in patients with impaired renal function. Dialysis does not affect the half-life or clearance of itraconazole or hydroxyitraconazole (see also section "Dosage and administration").

Children

Data on oral administration of itraconazole in children are limited. Clinical pharmacokinetic studies in children and adolescents aged 5 months to 17 years have been conducted using oral or intravenous itraconazole. Individual doses ranged from 1.5 to 12.5 mg/kg/day, administered once or twice daily.

When the same daily dose was administered twice daily compared to once daily, peak and trough concentrations were comparable to those observed with once-daily dosing in adults.

No significant relationship between itraconazole AUC and total clearance and patient age was observed; however, a weak correlation was noted between patient age, volume of distribution, Cmax, and terminal elimination of itraconazole. Apparent clearance and volume of distribution were dependent on patient body weight.

Clinical characteristics.

Indications.

• Vulvovaginal candidiasis;
• pityriasis versicolor;
• dermatomycoses caused by itraconazole-susceptible pathogens (Trichophyton spp., 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 first-line antifungal therapy cannot be used or when treatment with other antifungal agents is ineffective, which may be due to underlying disease, pathogen resistance, or drug toxicity):
• 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 AIDS patients to prevent recurrence of existing fungal infection.

Itraconazole should be prescribed for prophylaxis of fungal infections in patients with prolonged neutropenia when standard therapy is inadequate.

Contraindications.

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

Concomitant use of Esol medicinal product and CYP3A4 substrates is contraindicated (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use"). These include:

The Esol medicinal product should not be prescribed to patients with signs of ventricular dysfunction, such as congestive heart failure (present or in medical history), except for the treatment of life-threatening infections or other serious infections (see section "Special precautions and warnings").

The Esol medicinal product must not be used during pregnancy (except in life-threatening situations (see section "Use during pregnancy or breastfeeding")).

Women of childbearing potential who are taking the Esol medicinal product should use effective contraceptive methods during treatment with itraconazole and until the end of the menstrual cycle after completion of therapy.

Interaction with other medicinal products and other forms of interaction.

Itraconazole is predominantly metabolized by cytochrome CYP3A4. Other drugs that are metabolized via this pathway or that modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. Itraconazole is a potent inhibitor of CYP3A4 and
P-glycoprotein, as well as an inhibitor of breast cancer resistance protein (BCRP).

Itraconazole may alter the pharmacokinetics of other substances that share this metabolic or protein transport pathway.

Examples of drugs that may affect itraconazole plasma concentrations are listed by drug classes in Table 1.

Examples of drugs whose plasma concentrations may be affected by itraconazole are presented in Table 2. Due to the number of interactions, potential changes in safety or efficacy of interacting drugs are not fully accounted for. It is necessary to review the prescribing information of the interacting drug for additional details.

Interactions described in Tables 1 and 2 are classified as contraindicated, not recommended, or those requiring caution when used with itraconazole, based on the extent of concentration increase and safety profile of the interacting drug (see also sections "Contraindications" and "Special precautions and warnings" for further information). The interaction potential of the listed drugs was assessed based on pharmacokinetic studies of itraconazole and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g., ketoconazole) and/or in vitro data:

Contraindicated: under no circumstances should these drugs be used concomitantly or less than 2 weeks after discontinuation of itraconazole treatment.

Not recommended: concomitant use of these medicinal products and within 2 weeks after discontinuation of itraconazole treatment should be avoided, except when the expected benefit outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be closely monitored for signs or symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

Use with caution: careful monitoring is recommended when used concomitantly with itraconazole. Such patients should be closely observed for symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

The interactions listed in these tables were characterized in studies conducted with recommended doses of itraconazole. However, the extent of interaction may depend on the administered dose of itraconazole. A stronger interaction may occur at higher doses or with shorter dosing intervals. Extrapolation of results to other dosing regimens or different drugs should be done with caution.

After discontinuation of treatment, itraconazole concentration decreases to nearly undetectable levels in plasma within 7–14 days, depending on the dose and duration of treatment.

In patients with liver cirrhosis or in healthy volunteers receiving CYP3A4 inhibitors, the decline in plasma concentration may be even more gradual. This is particularly important at the start of therapy with drugs whose metabolism is affected by itraconazole (see section "Pharmacological properties").

Table 1

Examples of medicinal products that may affect itraconazole plasma concentrations

Table 2

Examples of medicinal products whose plasma concentrations may be affected by itraconazole

Special precautions for use.

Cross-sensitivity

There are no data regarding cross-sensitivity between itraconazole and other azole antifungal agents. Caution should be exercised when prescribing itraconazole to patients with hypersensitivity to other azoles.

Cardiac effects

In intravenous itraconazole studies, transient asymptomatic decreases in left ventricular ejection fraction were observed, which resolved before the next infusion. The clinical relevance of these findings for oral formulations has not been established.

It is known that itraconazole exerts a negative inotropic effect. Cases of congestive heart failure associated with its use have been reported. In spontaneous reports, the incidence of congestive heart failure was higher with a total daily dose of 400 mg compared to lower daily doses. Therefore, the risk of heart failure may increase in a dose-dependent manner with the total daily dose of itraconazole.

The medicinal product Esol should not be administered to patients with congestive heart failure or a history thereof, except when the expected benefit clearly outweighs the potential risk. In individual benefit-risk assessment, factors such as severity of the underlying condition, dosing regimen and duration of treatment (total daily dose), as well as individual risk factors for developing congestive heart failure, should be considered. These risk factors include pre-existing cardiac conditions such as ischemic heart disease or valvular heart disease; severe pulmonary diseases, including chronic obstructive pulmonary disease; renal impairment; or other conditions associated with edema. Such patients should be informed about symptoms of congestive heart failure, treatment should be administered cautiously, and symptoms of heart failure should be monitored. If such symptoms occur during treatment, the drug should be discontinued immediately.

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

Hepatic effects

Severe hepatotoxicity, including acute liver failure with fatal outcomes, has been reported rarely with itraconazole use. Most cases occurred in patients with pre-existing liver disease, those receiving systemic treatment, those with other serious underlying conditions, and/or those taking other hepatotoxic drugs. In some patients, no obvious risk factors for liver disease were identified. Some of these cases occurred within the first month of treatment, including during the first week. Therefore, monitoring of liver function is advisable in patients taking itraconazole. Patients should be informed about the need to seek immediate medical attention if symptoms of hepatitis develop, such as anorexia, nausea, vomiting, increased 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 itraconazole in patients with hepatic impairment are limited. This medicinal product should be used with caution in such patients. Close monitoring of patients with impaired liver function who are taking itraconazole is recommended. When considering treatment with other drugs metabolized by CYP3A4, the prolonged elimination half-life of itraconazole observed in clinical studies in patients with cirrhosis receiving single doses of itraconazole tablets should be taken into account.

Itraconazole is contraindicated in patients with elevated or abnormal liver enzyme levels, active liver disease, or manifestations of hepatotoxicity due to other medications, except in serious or life-threatening situations, and only if the expected benefit outweighs the risk of liver injury. In such cases, monitoring of liver function is required in patients with active liver disease or hepatotoxicity from other drugs (see also section "Pharmacokinetics").

Reduced gastric acidity

Absorption of itraconazole from tablets is reduced in conditions of low gastric acidity. In patients with reduced gastric acidity due to disease (e.g., achlorhydria) or those taking concomitant medications that reduce gastric acidity, it is recommended to take itraconazole with an acidic beverage (e.g., 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").

Elderly patients

Clinical data on the use of itraconazole in elderly patients are limited. The medicinal product should not be used in elderly patients unless the expected benefit outweighs the potential risk. In general, when selecting the itraconazole dose for elderly patients, consideration should be given to the higher likelihood of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or therapies with other medicinal products.

Renal impairment

Data on the oral use of itraconazole in patients with renal impairment are limited. Caution should be exercised when administering the drug to this patient group. The oral bioavailability of 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 with concomitant use of quinidine, which is contraindicated (see section "Interaction with other medicinal products and other forms of interaction"). Hearing usually recovers after discontinuation of itraconazole therapy, but in some patients, hearing loss is irreversible.

Immunocompromised patients

In some immunocompromised patients (e.g., those with neutropenia, AIDS, or organ transplant recipients), the oral bioavailability of itraconazole may be reduced.

Patients with life-threatening systemic fungal infections

Due to its pharmacokinetic properties (see section "Pharmacokinetics"), itraconazole tablets are not recommended for primary therapy of acute, life-threatening conditions caused by systemic fungal infections.

Patients with AIDS

For AIDS patients treated for systemic fungal infections such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (meningeal or non-meningeal) and at risk of relapse, the physician should evaluate the need for maintenance therapy.

Neuropathy

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

Cystic fibrosis

In patients with cystic fibrosis, variable therapeutic levels of itraconazole at steady state were observed after oral administration of itraconazole solution at a dose of 2.5 mg/kg twice daily. Itraconazole concentrations > 250 ng/mL at steady state were achieved in approximately 50% of patients aged 16 years and older, but in none of the patients under 16 years of age. If a patient does not show a clinical response to itraconazole, consideration should be given to switching to alternative therapy.

Cross-resistance

In cases of suspected systemic candidiasis caused by Candida species resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, susceptibility testing should be performed before initiating itraconazole therapy.

Interchangeability

Interchange between itraconazole tablets and oral solution is not recommended. This is because drug exposure is higher with the oral solution than with tablets when the same dose is administered.

Interaction potential

Concomitant use of itraconazole with certain medicinal products may lead to changes in the efficacy of itraconazole and/or the concomitant drug, serious or life-threatening adverse reactions, and/or sudden fatal outcomes. Medicinal products that are contraindicated, not recommended, or recommended for use with caution together with itraconazole are listed in the sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Excipients

The product contains sugar and lactose. In case of established intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Itraconazole should not be administered during pregnancy except in life-threatening conditions where the potential benefit to the mother outweighs the possible risk to the fetus (see section "Contraindications").

In animal studies, itraconazole showed reproductive toxicity.

Data on the use of itraconazole during pregnancy are limited. Cases of developmental abnormalities (skeletal, genitourinary, cardiovascular, and ocular malformations, chromosomal abnormalities, and multiple congenital anomalies) have been reported. However, a causal relationship with itraconazole has not been established. Epidemiological data on the effect of itraconazole in the first trimester of pregnancy (mainly in patients using it for short-term treatment of vulvovaginal candidiasis) did not show an increased risk of congenital malformations compared to women not exposed to teratogenic drugs.

Women of childbearing potential

Women of childbearing potential taking itraconazole should use reliable contraceptive methods throughout the treatment course and until the first menstrual period after completion of therapy.

Breastfeeding period

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

Fertility

In rats, itraconazole did not affect fertility in males or females at doses showing signs of general toxicity. The effect in humans is unknown.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the drug on reaction speed during driving or operating machinery have not been conducted. The possibility of adverse reactions such as dizziness, visual disturbances, and hearing loss (see section "Adverse reactions") should be considered, as these may negatively affect the ability to drive or operate machinery.

Method of administration and dosage.

Tablets should be taken orally immediately after food to ensure maximum drug absorption. Tablets should be swallowed whole.

Table 3

Treatment regimens for adults for each indication

Table 4

Dosing recommendations depending on the type of infection

Children

The safety and efficacy of itraconazole in children and adolescents under 18 years of age have not been established. Available data to date are described in the sections "Pharmacokinetics" and "Adverse reactions", but no recommendations for use can be provided.

Elderly patients

Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole is recommended for use in elderly patients only when the expected benefit outweighs the potential risk. In general, dose selection for elderly patients should be cautious, considering the higher frequency of impaired liver, kidney, or cardiac function, as well as concomitant diseases or other medicinal therapies (see section "Special precautions for use").

Patients with renal impairment

Clinical data on the use of oral formulations of itraconazole in patients with renal impairment are limited. The bioavailability of the drug following oral administration may be reduced in patients with renal insufficiency. Caution should be exercised when administering this medicinal product to such patients, and dose adjustment should be considered.

Patients with hepatic impairment

Clinical data on the use of oral formulations of itraconazole in patients with hepatic impairment are limited. Caution should be exercised when administering this medicinal product to such patients (see section "Pharmacokinetics").

Children.

The use of the drug in children is not recommended.

Overdose.

Symptoms and signs

In general, adverse reactions reported in cases of overdose had a similar profile to the adverse reactions occurring during itraconazole administration (see section "Adverse reactions").

Treatment

In case of overdose, supportive measures should be taken. If justified, activated charcoal may be administered. Itraconazole cannot be removed by hemodialysis. There is no specific antidote.

It is recommended to contact a toxicology center to obtain the latest recommendations on overdose management.

Adverse Reactions

Short description of the safety profile

The most commonly reported adverse reactions during clinical trials and spontaneous reporting with itraconazole were headache, abdominal pain, and nausea. The most serious adverse reactions included allergic reactions, heart failure/congestive heart failure/pulmonary edema, pancreatitis, severe hepatotoxicity (including several cases of acute liver failure resulting in death), and severe skin reactions. The frequencies of adverse reactions and other adverse reactions are listed below. For additional information on other serious effects, see section "Special precautions for use".

The adverse reactions listed below were derived from open-label and double-blind clinical studies using reference product capsules in 8,499 patients treated for dermatomycoses or onychomycosis, as well as from spontaneous reports.

The adverse reactions listed below are grouped by organ systems, with terms within each organ system category listed by frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated based on available data).

* See section "Special precautions for use".

Description of selected adverse reactions

The adverse reactions listed below are associated with the use of itraconazole and have been reported during clinical trials of the oral solution and intravenous solution, excluding injection site reactions, as this adverse reaction is specific only to the intravenous formulation.

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: heart failure, left ventricular dysfunction, 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 dysfunction, urinary incontinence.

General disorders and administration site conditions: generalized oedema, facial swelling, chest pain, pyrexia, pain, fatigue, chills.

Investigations: increased alanine aminotransferase, increased aspartate aminotransferase, increased alkaline phosphatase, increased lactate dehydrogenase, increased gamma-glutamyl transferase, increased liver enzymes, abnormalities in urine analysis.

Paediatric population

The safety of itraconazole capsules was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo-controlled trials; 9 open-label trials; 1 trial with an open phase followed by a double-blind phase). These patients received at least one dose of itraconazole capsules for the treatment of fungal infections, and safety data were collected.

Based on pooled safety data from these clinical trials, the commonly reported adverse reactions in children were: headache (3.0%), vomiting (3.0%), abdominal pain (2.4%), diarrhoea (2.4%), hepatic function abnormality (1.2%), arterial hypotension (1.2%), nausea (1.2%), and urticaria (1.2%). Overall, the adverse reaction profile in children is similar to that observed in adults, but with higher frequency.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

4 or 10 tablets in a blister; 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.