Sporaxol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPORAXOL (SPORAXOL)

Composition:

Active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

Excipients: spherical sugar (sucrose, corn starch, purified water), poloxamer 188, hypromellose 6 cP, micronized poloxamer 188, capsule (indigo carmine (E 132), quinoline yellow (E 104), titanium dioxide (E 171), purified water, gelatin).

Pharmaceutical form. Capsules.

Main physicochemical properties: opaque hard gelatin capsules size №0 with green cap and body, containing yellow-beige spherical microgranules.

Pharmacotherapeutic group. Antifungal agents for systemic use. 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 a key component of the fungal cell membrane, and inhibition of its synthesis underlies the antifungal effect.

Breakpoint values for itraconazole have been established only for Candida spp. For superficial fungal infections (CLSI M27-A2; breakpoints have not been established by EUCAST methodology), the CLSI breakpoints are: susceptible ≤0.125; susceptible dose-dependent 0.25–0.5; 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. The spectrum includes: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Candida spp., including C. albicans, C. glabrata, and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Coccidioides immitis, Pseudallescheria boydii, Penicillium marneffei, and other yeast and mold 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 fungal types not inhibited by itraconazole are the Zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., and Absidia spp.), Fusarium spp., Scedosporium prolificans, 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 (thus removing itraconazole from its target site). Cross-resistance among azole-class drugs 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

Maximum plasma concentration (Cmax) after oral administration is reached within 2 to 5 hours. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after repeated dosing. Steady-state concentrations are achieved within 15 days, with Cmax values of 0.5 µg/mL, 1.1 µg/mL, and 2.0 µg/mL after doses of 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal 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.

The pharmacokinetics of itraconazole have been studied in healthy volunteers and special patient populations after single and multiple doses.

Absorption

Itraconazole is rapidly absorbed after oral administration. Maximum plasma concentrations of unchanged drug after oral capsule administration are reached within 2–5 hours. The absolute bioavailability of itraconazole is 55%. Maximum bioavailability is observed when the drug is administered immediately after a high-fat meal.

Absorption of itraconazole capsules is reduced in patients with decreased gastric acidity, in patients taking acid-suppressing 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 interaction" and "Special precautions"). Absorption of itraconazole on an empty stomach in such patients increases if the medicinal product Sporaxol is taken with acidic beverages (e.g., non-diet cola). After a single 200 mg dose administered on an empty stomach with non-diet cola following ranitidine (an H2-receptor antagonist), absorption of itraconazole is comparable to that observed after administration of the drug alone (see section "Interaction with other medicinal products and other forms of interaction").

The concentration of itraconazole after capsule administration is lower than after administration of the oral solution at the same dose (see section "Special precautions").

Distribution

The majority of itraconazole is bound to plasma proteins (99.8%), with albumin being the main binding component (99.6% for the hydroxy metabolite). It also has high affinity for lipids. Only 0.2% of itraconazole in blood remains unbound. The apparent volume of distribution of itraconazole is substantial (>700 L), suggesting extensive tissue distribution: concentrations in the lungs, kidneys, liver, bones, stomach, spleen, and muscles were 2–3 times higher than in plasma. Accumulation of itraconazole in keratinized tissues, particularly skin, was four times higher than in plasma.

Biotransformation

Itraconazole is extensively metabolized in the liver, producing numerous metabolites. One such metabolite is hydroxy-itraconazole, which exhibits antifungal activity in vitro comparable to that of itraconazole. Plasma concentrations of hydroxy-itraconazole are approximately twice those of itraconazole.

In vitro studies indicate that CYP3A4 is the primary enzyme involved in the metabolism of itraconazole.

Elimination

Approximately 35% of itraconazole is excreted in urine as inactive metabolites and about 54% in feces. Renal excretion of unchanged drug accounts for less than 0.03% of the dose, while fecal excretion of unchanged drug ranges from 3% to 18%. Clearance of itraconazole decreases at higher doses due to saturable hepatic metabolism.

Since redistribution of itraconazole from keratinized tissues is negligible, elimination from these tissues is linked to epidermal regeneration. In contrast to plasma, skin concentrations remain detectable 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 treatment initiation, concentrations remain detectable for at least six months after the end 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 (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, total itraconazole concentrations, based on AUC, were comparable between the two groups.

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

Renal Impairment

Data on the use of oral itraconazole in patients with renal impairment are limited. A pharmacokinetic study using a single 200 mg dose of itraconazole (4 capsules of 50 mg) was conducted in three groups of patients with impaired renal function (uremia: n=7, hemodialysis: n=7, continuous ambulatory peritoneal dialysis: n=5). In patients with uremia (mean creatinine clearance 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, AUC 0–8h). Plasma concentration profiles showed substantial inter-subject variability in all three groups.

After a single intravenous dose, mean terminal 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.

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

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 have been conducted using itraconazole capsules, oral solution, and intravenous solution. Individual doses using 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 used. No significant dependence of itraconazole AUC and total clearance on patient age was observed; however, a weak relationship 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-sensitive agents (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 applied, or in case of treatment failure with other antifungal agents, 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 cryptococcosis;
• Maintenance therapy in AIDS patients to prevent recurrence of existing fungal infection.

Itraconazole is also prescribed for prophylaxis of fungal infection in patients with prolonged neutropenia when standard therapy is inadequate.

Contraindications.

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

Concomitant use of the medicinal product Sporaxol and CYP3A4 substrates is contraindicated (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). These include:

Concomitant use may increase the plasma concentration of these medicinal products, which may lead to intensification or prolongation of therapeutic and adverse reactions, potentially life-threatening. For example, increased concentrations of these medicinal products may result in prolonged QT interval and ventricular tachyarrhythmias, including torsade de pointes, with potentially fatal arrhythmias. These medicinal products are listed in the section "Interaction with other medicinal products and other forms of interaction".

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

The drug should not be used during pregnancy, except for the treatment of conditions that are life-threatening to the mother (see section "Use in pregnancy or lactation").

Women of childbearing potential should use effective contraceptive methods during treatment with itraconazole and until the end of the menstrual cycle after completion of treatment.

Interaction with other medicinal products and other forms of interaction

Itraconazole is primarily metabolized by cytochrome CYP3A4. Other drugs that are metabolized via this pathway or that modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. Itraconazole, in turn, may also affect the pharmacokinetics of other substances. Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, 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 the plasma concentration of itraconazole 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 refer to the prescribing information of the interacting drug for additional details.

Interactions described in Tables 1 and 2 are classified as contraindicated, not recommended, or requiring cautious use with itraconazole, depending on the degree of concentration increase and the safety profile of the interacting drug. The potential for interaction 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 be used concomitantly or within 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 dose of itraconazole 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 monitored for signs or symptoms of increased or prolonged pharmacological effect of itraconazole or adverse reactions, and the dose of itraconazole should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

Examples of medicinal products whose concentration increases when used concomitantly with itraconazole are listed in the table with corresponding recommendations. However, the extent of interaction may depend on the dose of itraconazole administered. A stronger interaction may occur with higher doses or shorter dosing intervals. Extrapolation of results to other dosing scenarios or different drugs should be done with caution.

After discontinuation of treatment, itraconazole concentrations decrease to levels nearly undetectable in plasma within 7–14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in patients who are concomitantly using CYP3A4 enzyme inhibitors, the drug should be discontinued gradually. This is especially important for medicinal products whose metabolism is affected by itraconazole.

Medicinal products that may affect the plasma concentration of itraconazole are presented by drug classes.

Table 1

Table 2

Drugs whose plasma concentrations may be affected by itraconazole, listed by drug classes

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 capsules to patients with hypersensitivity to other azoles.

Cardiac effects

During intravenous itraconazole studies in healthy volunteers, transient asymptomatic decreases in left ventricular ejection fraction were observed; these 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 the use of the drug have been reported. Spontaneous reports have indicated a higher incidence of heart failure with total daily doses of 400 mg compared to lower daily doses, suggesting that the risk of heart failure may increase with higher total daily doses of itraconazole.

The drug should not be administered to patients with congestive heart failure or a history of this condition, except when the expected benefit clearly outweighs the potential risk. When individually assessing the benefit-risk ratio, factors such as severity of the indication, 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, such as obstructive lung disease; renal insufficiency; or other conditions associated with edema. Such patients should be informed about symptoms of congestive heart failure, treatment should be administered cautiously, and symptoms should be monitored during therapy. If such symptoms occur during treatment, the drug should be discontinued immediately.

Calcium channel blockers may have a negative inotropic effect, which may be potentiated by 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 fatal liver failure, has been very rarely observed during treatment with itraconazole capsules. Most cases occurred in patients with a history of liver disease who were 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 the drug. 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. Treatment should be initiated in patients with elevated liver enzymes, active liver disease, or signs of hepatotoxicity from other drugs only if the expected benefit outweighs the risk of liver injury. In such cases, monitoring of liver enzymes is necessary.

Reduced gastric acidity

Reduced gastric acidity impairs the absorption of itraconazole from capsules. Patients who are taking Sporaxol simultaneously with agents that reduce gastric acidity (such as aluminum hydroxide) should maintain at least a 2-hour interval between administrations of these medicinal products. Patients with achlorhydria, such as those with AIDS or those taking H2-receptor antagonists or proton pump inhibitors, are recommended to take Sporaxol capsules with acidic beverages such as cola.

Use in children

Due to insufficient clinical data on the use of itraconazole capsules in pediatric patients, the capsules should be prescribed to children only when the potential benefit clearly outweighs the potential risk.

Elderly patients

Due to limited clinical data on the use of itraconazole in elderly patients, the drug should be administered to this patient group only when the expected benefit significantly outweighs the potential risks. Dosing in elderly patients should be individualized, taking into account the increased likelihood of impaired liver, kidney, or cardiac function, as well as concomitant diseases and therapies with other medicinal products.

Renal impairment

Available data on the use of oral itraconazole in patients with impaired renal function are limited. Caution should be exercised when administering the drug to this patient group. The bioavailability of itraconazole after oral administration may be reduced in patients with renal insufficiency. In such cases, dose adjustment may be considered.

Hearing loss

There have been reports of temporary or permanent hearing loss in patients taking 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 Sporaxol 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 Sporaxol may be reduced.

Patients with life-threatening systemic fungal infections

Due to pharmacokinetic properties (see section "Pharmacokinetics"), Sporaxol 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 who are at risk of relapse, the physician should evaluate the need for maintenance therapy.

Neuropathy

If neuropathy associated with the use of Sporaxol capsules occurs, treatment should be discontinued.

Carbohydrate metabolism disorders

Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not use 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 Sporaxol capsules.

Interaction potential

Concomitant use of itraconazole with certain medicinal products may lead to changes in the efficacy of itraconazole and/or the co-administered drugs, to life-threatening effects, and/or to sudden death.

Medicinal products that are contraindicated, not recommended, or recommended for use with caution together with itraconazole are listed in the section "Interaction with other medicinal products and other forms of interaction."

Use during pregnancy or breastfeeding

Pregnancy

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

In animal studies, itraconazole did not show reproductive toxicity. The effect in humans is unknown.

Limited data are available on the use of Sporaxol during pregnancy. During the post-marketing period, cases of developmental abnormalities have been reported, including skeletal malformations, genitourinary tract, cardiovascular system, and ocular organ defects, as well as chromosomal abnormalities and multiple congenital anomalies. A causal relationship with itraconazole use 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 Sporaxol capsules 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 are excreted in breast milk. Therefore, during lactation, the potential risk to the infant should be weighed against the expected benefit of treatment with Sporaxol for the mother. If treatment is necessary, the woman should discontinue breastfeeding.

Ability to influence reaction speed when driving 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 "Adverse reactions") should be considered, as these may lead to adverse consequences while driving or operating machinery.

Method of administration and dosage.

Administer orally. To ensure optimal absorption of the drug, Sporaxol capsules should be taken immediately after a meal. The capsules should be swallowed whole.

Table 2

Treatment regimens for adults for each indication

Optimal clinical and mycological effects are achieved 1–4 weeks after completion of treatment for skin infections, vulvovaginal and oropharyngeal candidiasis, and 6–9 months after completion of treatment for nail plate infections. This is due to the fact that elimination of itraconazole from skin, nail, and mucosal tissues occurs more slowly than from blood plasma.

The duration of treatment for systemic fungal infections is adjusted according to the mycological and clinical response to therapy.

Table 3

Systemic mycoses

Elderly patients

Since clinical data on the use of itraconazole capsules in elderly patients are limited, the drug should be prescribed to these patients only when the expected beneficial effect outweighs the potential risk.

Sporaxol should not be prescribed to elderly patients except when the expected benefit significantly outweighs the potential risks (see section "Special precautions").

Patients with renal impairment

The bioavailability of the drug after oral administration may be reduced in patients with renal insufficiency; dose adjustment should be considered (see section "Special precautions").

Patients with hepatic impairment

Data on the use of oral itraconazole in patients with hepatic insufficiency are limited. The drug should be used with caution in such patients.

Children

Since clinical data on the use of itraconazole capsules in children are limited, Sporaxol should not be prescribed to children except when the expected benefit significantly outweighs the potential risks (see section "Special precautions").

Overdose.

Symptoms. Manifestations of overdose were similar to the adverse reactions observed during administration of the drug at recommended doses (see section "Adverse reactions").

Treatment. In case of accidental overdose, supportive measures should be taken. If justified, activated charcoal may be administered. Itraconazole is not eliminated from the body by hemodialysis. There is no specific antidote.

Adverse Reactions

The most commonly reported adverse reactions during clinical trials and/or 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, serious hepatotoxicity (including some cases of fatal acute liver failure), and severe skin reactions. For additional information on other serious effects, see section "Special Warnings and Precautions for Use".

Adverse reactions are categorized by organ systems and frequency. Within each frequency grouping, adverse reactions are listed in order of decreasing severity. 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).

Infections and infestations: uncommon – upper respiratory tract infections, sinusitis, 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 – paresthesia, hypoesthesia, dysgeusia, tremor.

Eye disorders: rare – visual disturbances, including blurred vision and diplopia.

Ear and labyrinth disorders: rare – tinnitus, transient or permanent hearing loss*.

Cardiac disorders: rare – congestive heart failure*.

Respiratory, thoracic and mediastinal disorders: rare – dyspnea.

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

Hepatobiliary disorders: uncommon – liver function abnormalities; rare – severe hepatotoxicity (including isolated cases of fatal acute liver failure)*, 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, photosensitivity, alopecia.

Renal and urinary disorders: rare – polyuria.

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

General disorders and administration site conditions: rare – edema.

Investigations: rare – increased blood creatine phosphokinase level.

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

The following adverse reactions have been additionally reported during clinical trials with itraconazole oral solution and/or intravenous solution.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

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

Psychiatric disorders: confusion.

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

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 impairment, urinary incontinence.

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

Investigations: increased alanine aminotransferase level, increased aspartate aminotransferase level, increased alkaline phosphatase level, increased lactate dehydrogenase level, increased blood urea level, increased gamma-glutamyl transferase level, increased liver enzyme levels, 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 treatment of fungal infections, and safety data were collected. Based on pooled safety data from these clinical trials, the most frequently 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 is similar to that in adults, although the frequency of occurrence is higher in children.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Keep out of the reach and sight of children.

Packaging. 5 capsules in a strip, 2 strips in a cardboard pack. 6 capsules in a strip, 5 strips in a cardboard pack. 6 capsules in a strip, 1 strip in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Liconsa, S.A., Spain.

Manufacturer's address.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, 19200 Guadalajara, Spain.

Marketing Authorization Holder.

UAB “Farmlyga”.

Address of the Marketing Authorization Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.