Itrakon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ITROCON® (ITRAcoN)

Composition:

Active substance: itraconazole;

1 capsule contains itraconazole pellets equivalent to 100 mg of itraconazole;

Excipients: hypromellose (hydroxypropylmethylcellulose (E 5)), sucrose;

capsule shell composition: gelatin, titanium dioxide (E 171), azorubine (E 122), indigocarmine (E 132).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size № 0 or № 1. The body of the capsule is pink, the cap is blue. The capsule contents are granules of almost white to creamy color, spherical in shape.

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

Pharmacological Properties.

Pharmacodynamics.

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

For itraconazole, susceptibility breakpoints have been established only for Candida spp. in superficial fungal infections (CLSI M27-A2; breakpoints have not been defined by EUCAST methodology). The CLSI breakpoints are as follows: susceptible ≤ 0.125 µg/mL; susceptible-dose dependent 0.25–0.5 µg/mL; and resistant ≥ 1 µg/mL. Breakpoints have not been established for filamentous fungi.

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

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

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

Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. Described mechanisms include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole, and/or 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 antifungal agents has been observed within Candida species; however, resistance to one azole does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics.

General pharmacokinetic characteristics. Peak plasma concentrations after oral administration of itraconazole are reached within 2 to 5 hours. Due to non-linear pharmacokinetics, itraconazole accumulates in plasma following repeated dosing. Steady-state concentrations are generally achieved within 15 days, with Cmax values of 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 elimination half-life of itraconazole generally 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 decline 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 saturable hepatic metabolism at higher doses, the clearance of itraconazole decreases.

Absorption. Itraconazole is rapidly absorbed after oral administration. Maximum plasma concentrations of unchanged drug are achieved within 2–5 hours after oral administration of capsules. The absolute bioavailability of itraconazole is 55%. Maximum bioavailability is observed when the drug is taken immediately after a high-calorie meal.

Absorption of itraconazole capsules is reduced in patients with decreased gastric acidity, patients taking acid-suppressing agents (H2-receptor antagonists, proton pump inhibitors), or patients with achlorhydria due to certain diseases (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Absorption of itraconazole on an empty stomach in such patients increases if itraconazole capsules are taken with acidic beverages (e.g., non-diet cola). When a single 200 mg dose of itraconazole capsules was administered on an empty stomach with non-diet cola after ranitidine (an H2-receptor antagonist), absorption of itraconazole was comparable to that observed after administration of itraconazole capsules alone.

The concentration of itraconazole after administration of capsules is lower than after administration of the oral solution at the same dose (see section "Special Warnings and 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). It also has high affinity for lipids. Only 0.2% of itraconazole in blood remains unbound. The apparent volume of distribution of itraconazole is quite large (>700 L), suggesting extensive tissue distribution: concentrations in the lungs, kidneys, liver, bones, stomach, spleen, and muscles were 2–3 times higher than plasma concentrations. Accumulation of itraconazole in keratinous tissues, particularly skin, was four times higher than in plasma. Concentrations in cerebrospinal fluid are significantly lower than in plasma, but efficacy against infections localized in cerebrospinal fluid has been demonstrated.

Biological transformation. Itraconazole is extensively metabolized in the liver, forming numerous metabolites. In vitro studies indicate that CYP3A4 is the primary enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxyitraconazole, which exhibits antifungal activity in vitro comparable to that of itraconazole. Plasma concentrations of hydroxyitraconazole are approximately twice those of itraconazole.

Elimination. Approximately 35% of itraconazole is excreted as inactive metabolites in urine and about 54% in feces within one week after administration of the oral solution. Renal excretion of unchanged itraconazole and its active metabolite hydroxyitraconazole after intravenous administration accounts for less than 1% of the dose. Fecal excretion of unchanged drug ranges from 3% to 18%.

Special patient populations.

Hepatic impairment. Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole (1 capsule of 100 mg) was conducted in 6 healthy volunteers and 12 patients with cirrhosis. A statistically significant reduction in mean Cmax (by 47%) and a doubling of the elimination half-life (37±17 vs. 16±5 hours) were observed in cirrhotic patients compared to healthy volunteers. However, overall itraconazole concentrations based on AUC were comparable between the two groups.

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

Renal impairment. Data on the use of oral itraconazole in patients with renal dysfunction are limited. A pharmacokinetic study using a single 200 mg dose of itraconazole (4 capsules of 50 mg) was conducted in 3 groups of patients with renal impairment (uremia: n=7, hemodialysis: n=7, continuous ambulatory peritoneal dialysis: n=5). In patients with uremia (mean creatinine clearance of 13 mL/min × 1.73 m²), AUC-based concentrations were slightly reduced compared to healthy subjects. This 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-time profiles showed considerable inter-subject variability in all three groups.

After a single intravenous dose, mean terminal elimination half-life values in patients with mild (CrCl 50–79 mL/min), moderate (CrCl 20–49 mL/min), and severe (CrCl < 20 mL/min) renal impairment were similar to those in healthy volunteers (range 42–49 hours vs. 48 hours in patients with renal impairment and healthy volunteers, respectively). Total itraconazole concentrations based on AUC were reduced by 30% and 40% in patients with moderate and severe renal impairment, respectively, compared to healthy volunteers.

There are no available data on long-term use of itraconazole in patients with renal impairment. Dialysis does not affect the elimination half-life or clearance of itraconazole or hydroxyitraconazole.

Pediatric population. Data on the use of oral itraconazole in children are limited. Clinical pharmacokinetic studies in children and adolescents aged 5 months to 17 years have been conducted using itraconazole capsules, oral solution, and intravenous solution. Individual doses with capsules and oral solution ranged from 1.5 to 12.5 mg/kg/day, administered once or twice daily. Intravenous doses of 2.5 mg/kg as a single infusion or 2.5 mg/kg as infusions once or twice daily were administered. No significant dependence of itraconazole AUC or total clearance on age was observed; however, a weak relationship between age, volume of distribution, Cmax, and terminal elimination was noted. Apparent clearance and volume of distribution were body weight-dependent.

Clinical characteristics.

Indications.

• Vulvovaginal candidiasis;
• Pityriasis versicolor;
• Dermatomycoses caused by itraconazole-sensitive 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 when first-line antifungal therapy cannot be used or when treatment with other antifungal agents is ineffective, which may be due to underlying pathology, 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 patients with AIDS to prevent recurrence of existing fungal infections.

Itrason® can also be prescribed for prophylaxis of fungal infections in patients with prolonged neutropenia when standard therapy is insufficient.

Contraindications.

Itrason® capsules are contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.

Concomitant use of Itrason® and CYP3A4 substrates is contraindicated. These include:

Contraindication to the use of Itracon® capsules applies to patients with ventricular dysfunction, such as congestive heart failure, or a history of congestive heart failure, except for the treatment of life-threatening infections (see section "Special precautions").

Itracon® capsules should not be used during pregnancy, except for the treatment of life-threatening conditions in the pregnant woman (see section "Use during pregnancy or breastfeeding").

Women of childbearing potential should use effective contraceptive methods during treatment with Itracon® capsules and until the end of the menstrual cycle following 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, P-glycoprotein, and breast cancer resistance protein (BCRP). Itraconazole may alter the pharmacokinetics of other substances that share common metabolic or protein transport pathways.

Examples of medicinal products that may affect itraconazole plasma concentrations are listed by drug classes in Table 1 below. Examples of medicinal products whose plasma concentrations may be affected by itraconazole are listed in Table 2 below. Due to the large number of interactions, potential changes in safety or efficacy of interacting drugs are not included. Please refer to the prescribing information of the interacting medicinal products for additional details. The interactions described in these tables are classified as contraindicated, not recommended, or requiring cautious use with itraconazole, taking into account the extent of concentration increase and the safety profile of the interacting medicinal products (see also sections "Special precautions" and "Contraindications" for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies of itraconazole and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g., ketoconazole) and/or in vitro data:

• "Contraindicated": must not be used concomitantly with itraconazole and for up to two weeks after discontinuation of itraconazole therapy.
• "Not recommended": concomitant use of these medicinal products and during the 2 weeks following discontinuation of itraconazole therapy should be avoided, except when the therapeutic benefit outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, clinical monitoring is recommended to detect signs or symptoms of increased, prolonged, or adverse reactions of the co-administered drug, and dose reduction or interruption of the co-administered drug may be necessary. Therapeutic drug monitoring of the co-administered drug plasma concentration is recommended when needed.
• "Use with caution": careful monitoring is recommended when used concomitantly with itraconazole. Patients should be closely monitored for signs or symptoms of increased, prolonged, or adverse reactions of the co-administered drug, and dose reduction may be necessary. Therapeutic drug monitoring of the co-administered drug plasma concentration is recommended when needed.

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

After discontinuation of therapy, itraconazole plasma concentrations decline to nearly undetectable levels within 7 to 14 days, depending on the dose and duration of treatment. In patients with liver cirrhosis or in those concurrently taking CYP3A4 inhibitors, the decline in plasma drug concentration may be even more gradual. This is particularly relevant for medicinal products whose metabolism is affected by itraconazole. (See section "Pharmacodynamics").

Table 1: Examples of medicinal products that may affect itraconazole plasma concentrations, listed by drug classes.

Table 2 Examples of medicinal products whose plasma concentrations may be affected by itraconazole, presented by classes of medicinal products

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 Itacon® capsules to patients with hypersensitivity to other azoles.

Cardiac effects. In studies of intravenous itraconazole involving healthy volunteers, transient asymptomatic reduction in left ventricular ejection fraction was observed; this returned to baseline before the next infusion. The clinical relevance of these findings for oral formulations has not been established.

It is known that itraconazole has a negative inotropic effect, and 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 than with lower daily doses. Therefore, the risk of heart failure may increase depending on the total daily dose of itraconazole.

The drug should not be administered to patients with congestive heart failure or a history of congestive heart failure, except in cases where the expected benefit clearly outweighs the potential risk. When individually assessing the benefit-risk ratio, factors such as severity of diagnosis, dosing regimen, duration of treatment (total daily dose), and 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 disease; severe pulmonary diseases, including chronic obstructive pulmonary disease; renal insufficiency; or other conditions associated with edema. Such patients should be informed about symptoms of congestive heart failure, and treatment should be administered cautiously with monitoring for signs and symptoms of heart failure. If such symptoms occur during the course of treatment, Itacon® should be discontinued immediately.

Calcium channel blockers may have a negative inotropic effect, which may be potentiated by the similar 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. Rare cases of severe hepatotoxicity, including cases of acute liver failure resulting in death, have been reported during treatment with itraconazole capsules. Most of these cases occurred in patients with pre-existing liver disease who were being treated for systemic indications, had other serious illnesses, and/or were 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 the first week. Therefore, monitoring of liver function is advisable in patients taking Itacon®. Patients should be warned to seek immediate medical attention if symptoms of hepatitis develop, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed. Data on the use of oral itraconazole in patients with hepatic insufficiency are limited. This medicinal product should be used with caution in such patients. Close monitoring is recommended for patients with impaired liver function who are receiving itraconazole. When considering treatment with other medicinal products metabolized by CYP3A4, the prolonged elimination half-life of itraconazole observed in clinical studies in patients with cirrhosis who received single doses of itraconazole capsules should be taken into account.

Patients with elevated or abnormal liver enzyme levels, active liver disease, or manifestations of hepatotoxicity due to other medications should not be treated, except in life-threatening or serious situations where the expected benefit outweighs the risk. In such cases, monitoring of liver function is recommended in patients with active liver disease or hepatotoxicity due to other medications.

Reduced gastric acidity. Reduced gastric acidity impairs absorption of itraconazole from capsules. Patients with reduced gastric acidity due to disease (e.g., achlorhydria) or concomitant use of other medications (e.g., acid-reducing agents) are advised to take Itacon® capsules with acidic beverages (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").

Use in children.

The safety and efficacy of Itacon® in children under 18 years of age have not been established (see sections "Pharmacokinetics" and "Side effects").

Elderly patients. Clinical data on the use of itraconazole capsules in elderly patients are limited. Itacon® capsules should be used in elderly patients only if the benefit outweighs the potential risk. Dosing in elderly patients should be individualized, taking into account the increased likelihood of impaired hepatic, renal, or cardiac function, as well as concomitant diseases and use of other medicinal products.

Renal impairment. Data on the use of oral 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 insufficiency. In such cases, dose adjustment should be considered.

Hearing loss. Cases of temporary or permanent hearing loss have been reported in patients receiving itraconazole. In some cases, hearing loss occurred during concomitant use with 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 may be irreversible.

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

Patients with life-threatening systemic fungal infections. Due to pharmacokinetic properties (see section "Pharmacokinetics"), Itacon® capsules are not recommended for primary therapy of acute, life-threatening conditions caused by systemic fungal infections.

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

Neuropathy. If neuropathy occurs related to itraconazole use, the drug should be discontinued.

Cystic fibrosis. Variable therapeutic levels of itraconazole have been observed in patients with cystic fibrosis receiving a constant dose of oral itraconazole solution at 2.5 mg/kg twice daily. Steady-state concentrations > 250 ng/mL 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 respond to Itacon® capsules, consideration should be given to switching to alternative therapy.

Carbohydrate metabolism disorders. The medicinal product contains sucrose. Patients with diagnosed intolerance to certain sugars should consult their physician before taking this medicinal product. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

Cross-resistance. In systemic candidiasis, if there is suspicion that the Candida species causing the infection are resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, susceptibility testing should be performed before initiating treatment with Itacon® capsules.

Interchangeability. It is not recommended to interchange itraconazole capsules and oral itraconazole solution, as the oral solution has higher bioavailability than capsules when administered at the same oral doses.

Interaction potential. Concomitant use of itraconazole and certain medicinal products may lead to changes in the efficacy of itraconazole and/or the co-administered drug, serious or life-threatening adverse reactions, or sudden death. Medicinal products that are contraindicated, not recommended, or recommended for use with caution when co-administered with itraconazole are listed in section "Interaction with other medicinal products and other forms of interaction."

The medicinal product contains the azorubine dye, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Itacon® should not be prescribed to pregnant women except in life-threatening situations where the potential benefit to the mother outweighs the risk of negative effects on the fetus (see section "Contraindications").

In animal studies, itraconazole showed reproductive toxicity (see section "Pharmacokinetics").

Data on the use of itraconazole during pregnancy are limited. During the post-marketing period, cases of developmental abnormalities have been reported, including skeletal malformations, genitourinary tract abnormalities, cardiovascular system and visual organ defects, chromosomal abnormalities, and multiple congenital malformations. A causal relationship with itraconazole capsules has not been established. Epidemiological data on the effect of itraconazole in the first trimester of pregnancy (mainly in patients who used it for short-term treatment of vulvovaginal candidiasis) did not show an increased risk of congenital malformations compared to women who did not use teratogenic drugs.

Women of childbearing potential

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

Lactation

Very small amounts of itraconazole pass into breast milk. Therefore, during breastfeeding, the potential risk to the infant should be weighed against the expected benefit of treatment with Itacon® for the mother. In cases of uncertainty, breastfeeding should be discontinued.

Fertility

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

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the effect 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 "Side effects") should be considered, as these may negatively affect the ability to drive vehicles or operate machinery.

Administration and Dosage.

Itacon® capsules should be taken orally immediately after a meal to ensure maximum drug absorption. The capsules should be swallowed whole.

Treatment regimens for adults for each indication:

Table 3.

Dosage recommendations depend on the infection being treated.

Table 4.

The duration of treatment should be adjusted according to the clinical response.

Children.

The safety and efficacy of Itacon® in children and adolescents under 18 years of age have not been established. Available data are described in the sections “Pharmacokinetics” and “Adverse reactions”, but no dosage recommendations can be provided.

Elderly patients.

Clinical data on the use of Itacon® in elderly patients are limited. Itacon® should be prescribed to these patients only when the expected positive effect outweighs the potential risk. In general, dose selection for elderly patients should take into account the increased likelihood of impaired hepatic, renal, or cardiac function, as well as concomitant diseases or other medicinal therapies. See section (see section “Dosage and Administration”).

Patients with renal impairment.

Clinical data on the use of oral formulations of itraconazole in patients with impaired renal function 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 impaired hepatic function are limited. Caution should be exercised when administering this medicinal product to such patients (see section “Pharmacological properties. Pharmacokinetics”).

Children.

The use of Itacon® in children is not recommended (see section “Dosage and Administration”).

Overdose.

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

In case of overdose, supportive measures should be taken. Itraconazole cannot be removed by hemodialysis. There is no specific antidote. It is recommended to contact a poison control center for up-to-date recommendations on the management of overdose.

Adverse Reactions

The most commonly reported adverse reactions during clinical trials and spontaneous reports with itraconazole capsules were headache, abdominal pain, and nausea. The most serious adverse reactions included severe allergic reactions, heart failure/congestive heart failure/pulmonary edema, pancreatitis, severe hepatotoxicity (including several cases of acute liver failure with fatal outcome), and severe skin reactions.

The frequency and other adverse reactions are listed below.

The adverse reactions listed below were reported in open-label and double-blind clinical trials involving 8499 patients who received itraconazole capsules for the treatment of dermatomycoses or onychomycoses, as well as in spontaneous reports.

The adverse reactions listed below are grouped by system organ class, with individual terms listed by frequency within each group. 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, angioneurotic edema, anaphylactic reactions.

Metabolism and nutrition disorders: rare – hypertriglyceridemia.

Nervous system disorders: common – headache; rare – tremor, paresthesia, hyposthesia, dysgeusia.

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 system disorders: rare – dyspnea.

Gastrointestinal disorders: common – abdominal pain, nausea; uncommon – diarrhea, vomiting, constipation, dyspepsia, flatulence; rare – pancreatitis.

Hepatobiliary disorders: uncommon – liver function abnormalities; rare – severe hepatotoxicity (including several cases of severe acute liver failure with fatal outcome)*, hyperbilirubinemia.

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 – polyuria.

Reproductive system and breast disorders: uncommon – menstrual disorders; rare – erectile dysfunction.

General disorders: uncommon – edema.

Investigations: rare – increased blood creatine phosphokinase level.

* see section "Special Warnings and Precautions for Use".

Description of selected adverse reactions

The following adverse reactions associated with itraconazole use were reported in clinical trials of itraconazole capsules, oral solution, and intravenous solution, excluding injection site inflammation, which is specific only to the intravenous formulation.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

Metabolism and nutrition disorders: hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia.

Psychiatric disorders: confusion.

Nervous system disorders: peripheral neuropathy*, dizziness, somnolence.

Cardiac disorders: heart failure, left ventricular failure, tachycardia.

Vascular disorders: arterial hypertension, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: pulmonary edema, dysphonia, cough.

Gastrointestinal disorders: gastrointestinal disorders.

Hepatobiliary disorders: liver failure*, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary disorders: renal function abnormalities, urinary incontinence.

General disorders and administration site conditions: generalized edema, facial edema, chest pain, fever, pain, fatigue, chills.

Investigations: increased alanine aminotransferase, increased aspartate aminotransferase, increased alkaline phosphatase, increased lactate dehydrogenase, increased blood urea, increased gamma-glutamyl transferase, increased liver enzymes, abnormal urine test results.

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%), diarrhea (2.4%), liver function abnormalities (1.2%), arterial hypotension (1.2%), nausea (1.2%), and urticaria (1.2%). Overall, the adverse reaction profile in children is similar to that in adults, although the frequency of occurrence is higher in children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

5 capsules per blister; 3 blisters per carton.

4 or 6 capsules per blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer: JSC "Farmak"

Manufacturer's address and location of its business activities:

74, Kyrylivska Street, Kyiv, 04080, Ukraine