ORUNGAL®

INSTRUCTIONS for medical use of the medicinal product ORUNGAL® (ORUNGAL®)

Composition:

active ingredient: itraconazole;

1 capsule contains itraconazole 100 mg;

excipients: sucrose, hypromellose and polyethylene glycol 20,000;

capsule shell: titanium dioxide (E 171), indigo carmine (E 132), erythrosine (E 127), gelatin.

Medicinal form. Capsules.

Main physico-chemical properties: hard gelatin capsules consisting of a transparent pink body and an opaque blue cap. The capsule contents are creamy or almost white granules.

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.

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

In vitro studies have demonstrated that itraconazole inhibits the growth of a wide range of human-pathogenic fungi at concentrations typically ≤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 fungal types not inhibited by itraconazole are 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 (thereby removing itraconazole from its target site). Cross-resistance among azole 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

Peak plasma concentration after oral administration of itraconazole is reached within 2 to 5 hours. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma following repeated dosing. Steady-state concentrations are typically 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 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 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 concentration of unchanged drug is 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 in capsule form is reduced in patients with reduced gastric acidity, those taking acid-suppressing agents (H2-receptor antagonists, proton pump inhibitors), or those 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 when Orungal® capsules are taken with acidic beverages (e.g., non-diet cola). After administration of a single 200 mg dose of Orungal® with non-diet cola on an empty stomach following ranitidine (an H2-receptor antagonist), absorption of itraconazole was comparable to that after administration of Orungal® capsules alone.

The concentration of itraconazole after administration in capsule form is lower than after administration of the oral solution at the same dose (see section "Special Warnings and Precautions for Use").

Distribution

Itraconazole is highly 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 extensive (>700 L), suggesting wide 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 skin, was 4 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.

Biotransformation

Itraconazole is extensively metabolized in the liver, forming numerous metabolites. In vitro studies indicate that CYP3A4 is the primary enzyme involved in itraconazole metabolism. The major 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 varies between 3% and 18%.

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 both 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 renal dysfunction: uremia (n=7), hemodialysis (n=7), and chronic ambulatory peritoneal dialysis (n=5). In patients with uremia (mean creatinine clearance 13 mL/min × 1.73 m²), AUC-based concentrations were slightly lower than in healthy volunteers. The study did not demonstrate any significant effect of hemodialysis or chronic ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0–8h). 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 elimination half-life or clearance of itraconazole or hydroxyitraconazole.

Pediatric Patients

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 administration consisted of a single 2.5 mg/kg infusion or 2.5 mg/kg infused once or twice daily. No significant dependence of itraconazole AUC or 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-susceptible pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), such as 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 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 cryptococcosis;
• maintenance therapy in AIDS patients to prevent recurrence of existing fungal infection.

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

Contraindications.

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

Concomitant use of Orungal® and CYP3A4 substrates is contraindicated. Concurrent administration may increase plasma concentrations of these drugs, potentially leading to enhanced or prolonged therapeutic and adverse reactions, including life-threatening conditions. For example, elevated concentrations of these drugs may lead to QT interval prolongation and ventricular tachyarrhythmias, including ventricular fibrillation and potentially fatal arrhythmias. These medicinal products are listed in the section "Interaction with other medicinal products and other forms of interaction".

Orungal® capsules are 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 (see section "Special precautions").

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

Women of childbearing potential should use effective contraceptive methods during treatment with Orungal® capsules and throughout the menstrual cycle following completion of therapy.

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. Conversely, itraconazole may also affect the pharmacokinetics of other substances. Itraconazole is a potent inhibitor of CYP3A4 and
P-glycoprotein. When used concomitantly with other medicinal products, the prescribing information for these drugs should also be consulted regarding metabolic pathways and possible need for dose adjustments.

Medicinal products that may reduce itraconazole plasma concentrations

Medicinal products that reduce gastric acidity (acid-neutralizing agents such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) affect the absorption of itraconazole from capsules. Caution should be exercised when co-administering the following medicinal products with itraconazole capsules:

• when itraconazole is used concomitantly with agents that reduce gastric acidity, Orungal® capsules should be taken with acidic beverages such as non-diet cola;
• acid-neutralizing agents (e.g., aluminum hydroxide) should be administered at least 1 hour before or 2 hours after administration of Orungal® capsules;
• antifungal activity should be monitored, and the itraconazole dose increased if necessary.

Concomitant use of itraconazole with potent inducers of the CYP3A4 enzyme results in reduced bioavailability of itraconazole and hydroxyitraconazole, leading to a significant decrease in treatment efficacy. These medicinal products include:

• antibacterials: isoniazid, rifabutin (also see subsection "Medicinal products whose plasma concentrations are increased by itraconazole"), rifampicin;
• anticonvulsants: carbamazepine (also in subsection "Medicinal products whose plasma concentrations are increased by itraconazole"), phenobarbital, phenytoin;
• antivirals: efavirenz, nevirapine.

Concomitant use of potent CYP3A4 enzyme inducers with itraconazole is not recommended. Administration of the above-mentioned drugs should not be initiated within 2 weeks before, during, or within 2 weeks after itraconazole treatment, except when potential benefit clearly outweighs the risk. Antifungal activity should be closely monitored, and the itraconazole dose increased if necessary.

Medicinal products that increase itraconazole plasma concentrations

Potent inhibitors of the CYP3A4 enzyme may increase the bioavailability of itraconazole. Examples include:

• antibacterials: ciprofloxacin, clarithromycin, erythromycin;
• antivirals: darunavir boosted with ritonavir, fosamprenavir boosted with ritonavir, indinavir, ritonavir (also in subsection «Medicinal products whose plasma concentrations are increased by itraconazole»).

These agents should be used with caution when co-administered with itraconazole. Such patients should be closely monitored for symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose reduced if necessary. Monitoring of itraconazole plasma concentrations is recommended.

Medicinal products whose plasma concentrations are increased by itraconazole

Itraconazole and its main metabolite hydroxyitraconazole may inhibit the metabolism of drugs metabolized by the CYP3A4 enzyme and P-glycoprotein-mediated drug transport, potentially leading to increased plasma concentrations of these drugs and/or their metabolites. Such increased plasma concentrations may result in enhanced or prolonged therapeutic effects and the occurrence of adverse reactions. Concomitant administration of itraconazole and drugs metabolized by CYP3A4 that prolong the QT interval is contraindicated, as this may lead to ventricular tachyarrhythmias, including cases of fatal ventricular fibrillation. After discontinuation of treatment, itraconazole concentrations decrease to nearly undetectable levels in plasma within 7 to 14 days, depending on dose and duration of treatment. Gradual withdrawal is recommended in patients with liver cirrhosis or in patients who are concurrently using CYP3A4 enzyme inhibitors. This is particularly important for medicinal products whose metabolism is affected by itraconazole.

Concomitant medicinal products are grouped into the following categories:

Contraindicated: under no circumstances should these drugs be used concomitantly or within 2 weeks after completion of itraconazole treatment.

Not recommended: concomitant use of these medicinal products and use within 2 weeks after discontinuation of itraconazole treatment should be avoided, except when the benefit of treatment 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 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 symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

Table 1

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

a See also "Drugs that decrease itraconazole plasma concentration".

b See also "Drugs that increase itraconazole plasma concentration".

Drugs whose concentration is decreased by itraconazole.

Concomitant administration of itraconazole with meloxicam reduces the latter's concentration. Meloxicam should be prescribed with caution when used concomitantly with itraconazole, and therapeutic and adverse effects should be monitored. Dose adjustment of meloxicam is recommended.

Children.

Drug interaction studies have been conducted only in adults.

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 Orungal® capsules to patients with hypersensitivity to other azoles.

Effect on the heart.

In studies with intravenous Orungal® 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 Orungal® 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 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 when the expected benefit clearly outweighs the potential risk. When individually assessing the benefit-risk ratio, the following factors should be considered: severity of diagnosis, dosing regimen and duration of treatment (total daily dose), as well as individual risk factors for developing congestive heart failure. These risk factors include pre-existing heart conditions such as ischemic heart disease or valvular disease; severe lung diseases, including chronic obstructive pulmonary disease; renal impairment or other conditions associated with edema. Such patients should be informed about the symptoms of congestive heart failure, treatment should be administered cautiously, and symptoms of heart failure should be monitored. If such symptoms occur during treatment, Orungal® 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").

Effect on the liver.

Severe hepatotoxicity, including acute liver failure with fatal outcomes, has been very rarely reported with Orungal® capsules. Most of these 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 present. 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 Orungal®. Patients should be warned to seek immediate medical attention if symptoms of hepatitis occur, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or darkening of 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 this patient population. 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 capsules should be taken into account.

Treatment should be initiated only in patients with elevated liver enzymes, active liver disease, or manifestations of hepatotoxicity due to other drugs if the expected benefit outweighs the risk of liver injury. In such cases, monitoring of liver function is necessary.

Reduced gastric acidity.

Reduced gastric acidity impairs the absorption of itraconazole from Orungal® capsules. Patients with reduced gastric acidity due to disease (e.g., achlorhydria) or concomitant use of other drugs (e.g., acid-reducing agents) are recommended to take Orungal® capsules with acidic beverages (e.g., non-diet cola) (see section "Interaction with other medicinal products and other forms of interaction"). 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 Orungal® capsules in elderly patients are limited. Orungal® capsules should not be used in elderly patients unless the benefit of treatment outweighs the potential risk.

Hepatic impairment.

Limited data are available on the use of oral itraconazole in patients with impaired liver function. Caution should be exercised when administering the drug to this patient population.

Renal impairment.

Data on the use of oral itraconazole in patients with renal impairment are limited. The bioavailability of itraconazole after oral administration may be reduced in patients with renal impairment. Caution should be exercised when administering the drug to this patient population, and 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 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 Orungal® therapy; however, in some patients, hearing loss is irreversible.

Immunocompromised patients.

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

Patients with life-threatening systemic fungal infections.

Due to pharmacokinetic properties (see section "Pharmacokinetics"), Orungal® 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 occurs related to the use of Orungal® capsules, the drug 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 cases of 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, a sensitivity test should be performed before initiating treatment with Orungal® capsules.

Interchangeability.

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

Interaction potential.

Concomitant use of itraconazole and certain medicinal products may lead to altered efficacy of itraconazole and/or the concomitantly administered drug, serious or life-threatening adverse reactions, or sudden fatal outcomes. 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.

Orungal® 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 showed reproductive toxicity.

Data on the use of Orungal® during pregnancy are limited. In the post-marketing period, cases of developmental abnormalities have been reported, including skeletal malformations, genitourinary tract abnormalities, cardiovascular system and eye organ defects, chromosomal abnormalities, and multiple congenital malformations. A causal relationship with Orungal® capsules has not been established.

Epidemiological data on the effect of Orungal® in women during the first trimester of pregnancy (used primarily 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 Orungal® capsules should use reliable contraceptive methods throughout the entire course of treatment and until the first menstrual period after completion of treatment.

Breastfeeding period.

Very 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 with Orungal® for the mother. In cases of uncertainty, the woman should discontinue breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect on reaction speed when 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, which may lead to negative consequences during driving or operating machinery.

Method of Administration and Dosage.

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

Table 2

Treatment regimens for adults for each indication:

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

Table 3

Elderly patients.

The use of Orungal® in elderly patients is not recommended (see section "Special instructions").

Patients with renal function impairment.

Clinical data on the use of oral formulations of itraconazole in patients with renal function 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 function impairment.

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

Children.

The use of Orungal® in children is not recommended (see section "Special instructions").

Overdose.

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").

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

Adverse Reactions

The most commonly reported adverse reactions during clinical trials and spontaneous reports with Orungal® 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 outcomes), and severe skin reactions. The frequency of adverse reactions and other reported adverse reactions are listed below.

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

The adverse reactions listed below are grouped by system organ classes; within each group, reactions are listed by frequency. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000).

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 – paresthesia, hypoesthesia, dysgeusia.

Eye disorders:

• Rare – visual disturbances (including diplopia and blurred vision).

Ear and labyrinth disorders:

• Rare – transient or permanent hearing loss, tinnitus.

Cardiac disorders:

• Unknown frequency – congestive heart failure*.

Respiratory, thoracic and mediastinal disorders:

• Rare – dyspnea.

Gastrointestinal disorders:

• Common – abdominal pain, nausea;
• Uncommon – diarrhea, vomiting, constipation, dyspepsia, flatulence;
• Rare – pancreatitis.

Hepatobiliary disorders:

• Uncommon – hepatic function abnormalities;
• Rare – severe hepatotoxicity (including several cases of severe acute liver failure with fatal outcomes)*, 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;
• Unknown frequency – erectile dysfunction.

General disorders and administration site conditions:

• Uncommon – edema.

Investigations:

• Rare – increased blood creatine phosphokinase.

* 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 Orungal® capsules, oral solution, and intravenous solution, excluding injection site reactions, which are 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, tremor.

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 gamma-glutamyl transferase, increased liver enzymes, abnormalities in urine analysis.

Children.

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

Based on pooled safety data from these clinical trials, the most commonly reported adverse reactions in children were: headache (3.0%), vomiting (3.0%), abdominal pain (2.4%), diarrhea (2.4%), hepatic 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. 3 years.

Storage conditions.

Store out of reach of children at temperatures not exceeding 30 °C.

Packaging. 4 capsules per blister, 7 blisters per cardboard box, or 5 capsules per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Janssen-Cilag S.p.A. / Janssen Cilag S.p.A.

Manufacturer's address and place of business.

Via C. Janssen, 04100 Borgo S. Michele, Latina, Italy / Via C. Janssen, 04100 Borgo S. Michele, Latina, Italy.