Itrungar

Triazole derivatives

Itrungar (Itraconazole)

Indications

Treatment of mycoses, caused by itraconazole-susceptible agents in patients without immune system disorders:
- gynaecological diseases: vulvovaginal candidiasis;
- dermatological diseases: dermatomycosis, pityriasis versicolor;
- ophthalmological diseases: mycotic keratitis;
- oral candidiasis;
- onychomycoses, caused by dermatophytes, yeast, molds;
- systemic mycoses: systemic aspergillosis or candidiasis, cryptococcosis (including cryptococcal meningitis): patients with immune system disorders and all patients with cryptococcosis of the central nervous system the preparation is indicated only in case of ineffectiveness of the therapy with other atimycotic preparations;
- histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other systemic mycoses, which occur very seldom, or tropical mycoses.

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INSTRUCTION

for medical use of the medicinal product

ITRUNGAR

Composition:

active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

excipients:

pellets contain: hydroxypropyl methylcellulose, corn starch, saccharose;

capsule coat contains:

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

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

Pharmaceutical form. Capsules.

Basic physical and chemical properties: hard gelatine capsules with a yellow body and green cap or vice versa (size 0); capsule contents – white to grey pellets.

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

Pharmacological properties.

Pharmacodynamics.

Itraconazole is a triazole derivative with a broad spectrum of antifungal activity. In vitro studies have shown that itraconazole inhibits ergosterol synthesis in fungal cells. Ergosterol is an essential component of fungal cell membranes; its synthesis inhibition provides antifungal efficacy.

Clinical breakpoints have only been established for Candida spp. in relation to itraconazole. For superficial mycotic infections (CLSI M27-A2), breakpoints have not been set according to the EUCAST methodology. CLSI breakpoints: susceptible ≤0.125 µg/mL; dose-dependent susceptible 0.25–0.5 µg/mL; resistant ≥1 µg/mL. No breakpoints have been established for mycelial fungi.

In vitro studies have shown that itraconazole inhibits the growth of a broad spectrum of human pathogenic fungi, typically at concentrations ≤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 fungi varieties.

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

Fungi not inhibited by itraconazole include zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., Absidia spp.), Fusarium spp., Scedosporium proliferans, and Scopulariopsis spp.

Azole resistance develops slowly and usually results from multiple genetic mutations. Described mechanisms include overexpression of ERG11 (encoding the target enzyme 14α-demethylase), point mutations in ERG11 reducing itraconazole binding affinity, and overexpression of efflux transporters (increasing itraconazole efflux from fungal cells). Cross-resistance among azole drugs has been observed in Candida species, but resistance to one azole does not necessarily imply resistance to others. Resistance in Aspergillus fumigatus to itraconazole has been reported.

Pharmacokinetics

General pharmacokinetic characteristics

The peak plasma concentration is reached within 2 to 5 hours after oral administration. Due to non-linear pharmacokinetics, itraconazole accumulates in plasma after repeated dosing. Steady-state concentrations are generally achieved within 15 days, with C_max 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 ranges from 16 to 28 hours after a single dose and increases to 34–42 hours after repeated dosing. After treatment discontinuation, plasma levels decline to nearly undetectable levels within 7–14 days depending on dose and duration. The mean plasma clearance following IV administration is 278 mL/min. Saturable hepatic metabolism causes reduced clearance at higher doses.

Absorption

Itraconazole is rapidly absorbed following oral administration. Maximum plasma concentrations of the unchanged drug occur within 2–5 hours. Absolute bioavailability is 55%. Bioavailability is highest when itraconazole capsules are taken immediately after a full meal.

Absorption from capsules is reduced in patients with decreased gastric acidity, such as those on acid-suppressive therapy (e.g., H₂-antagonists, proton pump inhibitors) or those with achlorhydria due to certain diseases (see sections “Precautions for use” and “Interactions with other medicinal products and other forms of interaction”). In these patients, absorption can be improved by co-administering capsules with acidic beverages (e.g., non-diet cola). When 200 mg of Itrungar was administered on an empty stomach with non-diet cola after ranitidine, H₂-antagonists, absorption was comparable to that of Itrungar capsules administered alone.

Plasma concentrations of itraconazole after capsule use are lower than those after equivalent oral solution doses (see section “Precautions for use”).

Distribution

Itraconazole is highly protein-bound in plasma (99.8%), mainly to albumin (99.6% for its hydroxy metabolite), and has a high affinity for lipids. Only 0.2% of circulating itraconazole remains unbound. The apparent volume of distribution exceeds 700 L, indicating extensive tissue distribution. Concentrations in lungs, kidneys, liver, bones, stomach, spleen, and muscles are 2–3 times higher than plasma levels. Accumulation in keratinous tissues, especially skin, is about 4 times that in plasma. CSF concentrations are much lower than plasma, but efficacy has been demonstrated for infections localized in the CSF.

Biotransformation

Itraconazole is extensively metabolized in the liver, forming many metabolites. In in vitro studies, CYP3A4 was identified as the major enzyme involved. The main metabolite, hydroxy-itraconazole, has in vitro antifungal activity comparable to that of itraconazole. Plasma concentrations of hydroxy-itraconazole are approximately twice those of itraconazole.

Elimination

About 35% of the itraconazole dose is excreted in urine as inactive metabolites, and about 54% in faeces within one week after dosing with the oral solution. Less than 1% of the IV dose of itraconazole and hydroxy-itraconazole is renally excreted unchanged. Between 3–18% of unchanged itraconazole is eliminated in faeces.

Special patient populations

Hepatic impairment

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

No data are available regarding 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 with 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, chronic ambulatory peritoneal dialysis: n=5). In uremic patients with a mean creatinine clearance of 13 mL/min × 1.73 m², AUC-based plasma concentrations were slightly lower compared to those in healthy subjects. The study did not show any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (T_max, C_max, AUC_0-8h). Time-concentration profiles showed substantial inter-subject variability in all three groups.

Following a single intravenous dose, mean terminal half-lives 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 (42–49 hours in patients with renal impairment vs. 48 hours in healthy subjects). Total itraconazole exposure (based on AUC) was reduced by approximately 30% and 40% in patients with moderate and severe renal impairment, respectively, compared with 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 hydroxy-itraconazole.

Paediatric population

Data on the use of oral itraconazole in children are limited. Clinical pharmacokinetic studies have been conducted in children and adolescents aged 5 months to 17 years using itraconazole capsules, oral solution, and intravenous solution. Individual doses using the capsule and oral solution formulations ranged from 1.5 to 12.5 mg/kg/day, administered once or twice daily. Intravenous administration included single doses of 2.5 mg/kg or infusions of 2.5 mg/kg once or twice daily.

No significant correlation was found between AUC and age or total body clearance of itraconazole, although weak correlations were observed between age and volume of distribution, C_max, and terminal elimination of itraconazole. Apparent clearance and volume of distribution were influenced by body weight.

Clinical particulars

Indications

- Vulvovaginal candidiasis;
- Pityriasis versicolor;
- Dermatomycoses caused by itraconazole-sensitive 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 has proven ineffective 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 patients with AIDS to prevent relapse of existing fungal infections.

Itrungar is also indicated for the prevention of fungal infections in patients with prolonged neutropenia in cases where standard therapy is insufficient.

Contraindications

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

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

Analgesics; Anaesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Systemic antibacterials; antimycobacterial agents; systemic antifungals
Isavuconazole
Anthelmintics; Antiprotozoals
Halofantrine
Systemic antihistamines
Astemizole	Mizolastine	Terfenadine
Antineoplastic agents
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukaemia during initiation and dose titration phase)
Antiplatelet agents
Dabigatran	Ticagrelor
Systemic antivirals
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
Cardiovascular system (agents acting on the renin–angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiotherapy; diuretics)
Aliskiren	Eplerenone	Quinidine
Bepridil	Finerenone	Ranolazine
Disopyramide	Ivabradine	Sildenafil (for pulmonary hypertension)
Dofetilide	Lercanidipine
Dronedarone	Nisoldipine
Gastrointestinal medicines, including antidiarrheals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride	Domperidone	Naloxegol
Lipid-modifying agents
Lovastatin	Lomitapide	Simvastatin
Psychoanaleptics; psycholeptics (e.g. antipsychotics, anxiolytics and hypnotics)
Lurasidone	Pimozide	Sertindole
Oral midazolam	Quetiapine	Triazolam
Medicinal products affecting the urinary system
Avanafil	Darifenacin	Solifenacin (in patients with severe renal or moderate to severe hepatic impairment)
Dapoxetine	Fesoterodine (in patients with moderate or severe renal or hepatic impairment)	Vardenafil (in patients aged 75 years and older)
Other medicinal products and substances
Colchicine (in patients with renal or hepatic impairment)	Eliglustat (in patients who are CYP2D6 poor (PM), intermediate (IM), or extensive (EM) metabolizers taking a strong or moderate CYP2D6 inhibitor)

The use of the medicinal product 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 or other serious infections (see section "Precautions for use").

The medicinal product should not be used during pregnancy, except for the treatment of life-threatening conditions in the mother (see section "Pregnancy and lactation").

Women of childbearing potential must use effective contraception throughout the entire course of treatment with itraconazole and until completion of the menstrual cycle following the end of therapy.

Interaction with other medicinal products and other forms of interaction

Itraconazole is primarily metabolised by the cytochrome CYP3A4 enzyme. Other medicinal products that are metabolised via this pathway or that modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. Itraconazole is a potent inhibitor of CYP3A4, a P-glycoprotein inhibitor, and an inhibitor of breast cancer resistance protein (BCRP).

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

Examples of medicinal products that may affect plasma concentrations of itraconazole are listed by pharmacological class in Table 1 below.

Examples of medicinal products whose plasma concentrations may be affected by itraconazole are listed in Table 2 below. Potential changes in the safety or efficacy of the interacting products are not taken into account; refer to the respective Summary of Product Characteristics (SmPC) of the interacting product for further information.

Combinations of itraconazole with medicinal products listed in Tables 1 and 2 are classified as contraindicated, not recommended, or to be used with caution depending on the extent of concentration increase and the safety profile of the interacting product (see also sections “Contraindications” and “Special warnings and precautions for use”). The interaction potential of the listed products was evaluated based on pharmacokinetic studies of itraconazole or other strong CYP3A4 inhibitors (e.g., ketoconazole) in humans and/or in vitro data:

- "Contraindicated": the medicinal product must not be co-administered with itraconazole under any circumstances and for two weeks after discontinuation of itraconazole.
- "Not recommended": concomitant use and use within 2 weeks of discontinuing itraconazole should be avoided unless the benefit outweighs the potential risk of adverse effects. If concomitant use cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged pharmacological effects of the co-administered medicinal product is recommended, and its dose should be reduced or discontinued as necessary. Plasma concentrations of the co-administered drug may be monitored where appropriate.
- "Use with caution": close monitoring is recommended during concomitant use with itraconazole. Patients should be monitored carefully for signs or symptoms of increased or prolonged pharmacological effects of the co-administered medicinal product, and the dose should be reduced if necessary. Monitoring of plasma concentrations of the co-administered drug may be considered.

The interactions listed in these tables were characterized in studies using the recommended doses of itraconazole. However, the degree of interaction may vary depending on the itraconazole dose administered. A stronger interaction may occur with higher doses or shorter dosing intervals. Extrapolation of results to other dosing regimens or medicinal products should be performed with caution.

After discontinuation of treatment, plasma concentrations of itraconazole decline to below the quantifiable limit within 7–14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or those receiving concomitant CYP3A4 inhibitors, the decline may be more gradual. This is especially relevant for medicinal products whose metabolism is affected by itraconazole (see section "Pharmacokinetics").

Table 1

Medicinal products that may affect plasma concentrations of itraconazole

Medicinal Products (oral single dose unless otherwise stated)

Expected/Potential Impact on Itraconazole Levels:

↑ increase

↔ no changes

↓ decrease

Clinical comment (see also the information above, as well as the sections “Contraindications” and “Precautions for use”)

Systemic antibacterials; antimycobacterial agents

Isoniazid

Likely decreases Itraconazole concentration (not directly studied)

Not recommended

Rifampicin 600 mg orally once daily

Itraconazole AUC ↓

Not recommended

Rifabutin 300 mg orally once daily

Itraconazole C_max ↓ 71 %, AUC ↓ 74 %

Not recommended

Ciprofloxacin 500 mg orally twice daily

Itraconazole C_max ↑ 53 %, AUC ↑ 82 %

Use with caution

Erythromycin 1 g

Itraconazole C_max ↑ 44 %, AUC ↑ 36 %

Use with caution

Clarithromycin 500 mg orally twice daily

Itraconazole C_max ↑ 90 %, AUC ↑ 92 %

Use with caution

Antiepileptic drugs

Carbamazepine, Phenobarbital

Likely decrease Itraconazole concentration (not directly studied)

Not recommended

Phenytoin 300 mg orally once daily

Itraconazole C_max ↓ 83 %, AUC ↓ 93 %

Hydroxy-itraconazole C_max ↓ 84 %, AUC ↓ 95 %

Not recommended

Antineoplastic drugs

Idelalisib

Likely increases Itraconazole concentration (not directly studied)

Use with caution

Systemic antivirals

Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)

Likely increase Itraconazole concentration (not directly studied)

Contraindicated

Efavirenz 600 mg

Itraconazole C_max ↓ 37 %, AUC ↓ 39 %

Hydroxy-itraconazole C_max ↓ 35 %, AUC ↓ 37 %

Not recommended

Nevirapine 200 mg orally once daily

Itraconazole C_max ↓ 38 %, AUC ↓ 62 %

Not recommended

Cobicistat, darunavir (boosted), elvitegravir (boosted with ritonavir), fosamprenavir (boosted with ritonavir), ritonavir, saquinavir (boosted with ritonavir)

Likely increase Itraconazole concentration (not directly studied)

Use with caution

Indinavir 800 mg orally three times daily

Itraconazole concentration ↑

Use with caution

Calcium channel blockers

Diltiazem

Likely increases Itraconazole concentration (not directly studied)

Use with caution

Medicines for treating disorders associated with increased or decreased acidity

Antacids (aluminium, calcium, magnesium or sodium bicarbonate), H₂ receptor antagonists (e.g. cimetidine, ranitidine), proton pump inhibitors (e.g. lansoprazole, omeprazole, rabeprazole)

Itraconazole C_max ↓, AUC ↓

Use with caution

Respiratory system drugs

Lumacaftor/ivacaftor 200/250 mg orally twice daily

Itraconazole concentration ↓

Not recommended

Other drugs and substances

St. John’s wort

(Hypericum perforatum)

Likely decreases itraconazole concentration (not directly studied)

Not recommended

Table 2.

Examples of drugs whose plasma concentrations may be affected by itraconazole

Medicinal Products (oral single dose unless otherwise stated)	Expected/Potential Impact on Itraconazole Levels: ↑ increase ↔ no changes ↓ decrease	Clinical comment (see also the information above, as well as the sections “Contraindications” and “Precautions for use”)
Analgesics; anesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Eletriptan, fentanyl	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Alfentanil, buprenorphine (IV and sublingual), cannabinoids, methadone, sufentanil	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Oxycodone 10 mg orally	Oxycodone orally C_max ↑ 45 %, AUC ↑ 2.4 times	Use with caution
Oxycodone 0.1 mg/kg IV	Oxycodone IV AUC ↑ 51 %	Use with caution
Systemic antibacterials; antimycobacterials; systemic antimycotics
Isavuconazole	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated
Bedaquiline	Itraconazole likely increases concentrations of this drug (not directly studied)	Not recommended
Rifabutin 300 mg orally once daily	Rifabutin concentration ↑ (volume unknown)	Not recommended
Clarithromycin 500 mg orally twice daily	Clarithromycin concentration ↑	Use with caution
Delamanid	Itraconazole likely increases concentrations of this drug (not directly studied)	Use with caution
Antiepileptic drugs
Carbamazepine	Itraconazole likely increases concentrations of this drug (not directly studied)	Not recommended
Anti-inflammatory and antirheumatic drugs
Meloxicam 15 mg	Meloxicam C_max ↓ 64 %, AUC ↓ 37 %	Use with caution
Anthelmintic; antiprotozoal drugs
Halofantrine	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated
Artemether-lumefantrine, praziquantel	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Quinine 300 mg	Quinine C_max ↔, AUC ↑ 96 %	Use with caution
Systemic antihistamines
Astemizole, mizolastine, terfenadine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Ebastine 20 mg	Ebastine C_max ↑ 2.5 times, AUC ↑ 6.2 times Carebastine C_max ↔, AUC ↑ 3.1 times	Not recommended
Bilastine, rupatadine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Antineoplastic drugs
Irinotecan	Itraconazole likely increases Irinotecan and active metabolite levels (not directly studied)	Contraindicated
Venetoclax	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated in patients with chronic lymphocytic leukaemia during dose initiation and titration. Otherwise, not recommended unless the benefits outweigh the risks. Refer to venetoclax prescribing information.
Axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, crizotinib, dabrafenib, dasatinib, docetaxel, everolimus, glasdegib, ibrutinib, lapatinib, nilotinib, pazopanib, regorafenib, sunitinib, temsirolimus, trabectedin, trastuzumab, emtansine, vinca alkaloids (e.g., vinflunine, vinorelbine)	Itraconazole likely increases concentrations of these drugs (not directly studied), with the exception of Cabazitaxel and Regorafenib. There are no statistically significant changes in Cabazitaxel exposure, but there is considerable variability in the results. The AUC of Regorafenib is expected to decrease (based on the active fraction).	Not recommended
Cobimetinib 10 mg	Cobimetinib C_max ↑ 3.2 times, AUC ↑ 6.7 times	Not recommended
Entrectinib	Entrectinib C_max ↑73 %, AUC ↑ 6.0 times	Not recommended
Olaparib 100 mg	Olaparib C_max ↑ 40 %, AUC ↑ 2.7 times	Not recommended
Talazoparib	Talazoparib C_max ↑ 40 %, AUC ↑ 56 %	Not recommended
Alitretinoin (oral), bortezomib, brentuximab vedotin, erlotinib, idelalisib, imatinib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, tretinoin (oral)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Busulfan 1 mg/kg every 6 hours	Busulfan C_max ↑, AUC ↑	Use with caution
Gefitinib 250 mg	Gefitinib 250 mg C_max ↑, AUC ↑ 78 %	Use with caution
Pemigatinib	Pemigatinib C_max ↑ 17 %, AUC ↑ 91 %	Use with caution
Antiplatelet drugs
Dabigatran, ticagrelor	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Cilostazol, coumarins (e.g. warfarin)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Antiviral drugs for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase paritaprevir concentration	Contraindicated
Elbasvir/grazoprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Cobicistat, elvitegravir (boosted with ritonavir), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Indinavir 800 mg orally 3 times a day	Indinavir C_max ↔, AUC ↑	Use with caution
Cardiovascular system (agents affecting the renin-angiotensin system; antihypertensive drugs; beta-blockers; calcium channel blockers; cardiac therapy; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, finerenone, ivabradine, lerkanidipine, nisoldipine, ranolazine, sildenafil (pulmonary hypertension)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Aliskiren 150 mg	Aliskiren C_max ↑ 5.8 times, AUC ↑ 6.5 times	Contraindicated
Quinidine 100 mg	Quinidine C_max ↑ 59 %, AUC ↑ 2.4 times	Contraindicated
Felodipine 5 mg	Felodipine C_max ↑ 7.8 times, AUC ↑ 6.3 times	Not recommended
Riociguat, tadalafil (pulmonary hypertension)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (e.g., amlodipine, isradipine, nifedipine, nimodipine), verapamil	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Digoxin 0.5 mg	Digoxin C_max ↑ 34 %, AUC ↑ 68 %	Use with caution
Nadolol 30 mg	Nadolol C_max ↑ 4.7 times, AUC ↑ 2.2 times	Use with caution
Corticosteroids for systemic use; drugs for obstructive airway diseases
Ciclesonide, salmeterol	Itraconazole likely increases concentrations of Salmeterol and the active metabolite of Ciclesonide (not directly studied)	Not recommended
Budesonide inhalation 1 mg single dose	Budesonide inhalation C_max ↑ 65 %, AUC ↑ 4.2 times Budesonide (other forms) concentration ↑	Use with caution
Dexamethasone IV 5 mg Dexamethasone oral 4.5 mg	Dexamethasone IV: C_max ↔, AUC ↑ 3.3 times Dexamethasone oral: C_max ↑ 69 %, AUC ↑ 3.7 times	Use with caution
Fluticasone inhalation 1 mg twice daily	Fluticasone concentration ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone oral C_max ↑ 92 %, AUC ↑ 3.9 times Methylprednisolone IV AUC ↑ 2.6 times	Use with caution
Fluticasone nasal	Itraconazole likely increases concentrations of intranasally administered Fluticasone (not directly studied)	Use with caution
Medications for diabetes mellitus
Repaglinide 0.25 mg	Repaglinide C_max ↑ 47 %, AUC ↑ 41 %	Use with caution
Saxagliptin	Itraconazole likely increases Saxagliptin concentrations (not directly studied)	Use with caution
Gastrointestinal agents, including antidiarrheals, intestinal anti-inflammatory/anti-infective drugs; antiemetics and anti-nausea drugs; laxatives; drugs for functional gastrointestinal disorders
Cisapride, naloxegol	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Domperidone 20 mg	Domperidone C_max ↑ 2.7 times, AUC ↑ 3.2 times	Contraindicated
Aprepitant, loperamide, netupitant	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Itraconazole likely increases Sirolimus concentrations (not directly studied)	Not recommended
Cyclosporine, tacrolimus	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Tacrolimus IV 0.03 mg/kg once daily	Tacrolimus IV concentration ↑	Use with caution
Lipid-regulating agents
Lomitapide	Itraconazole likely increases Lomitapide concentrations (not directly studied)	Contraindicated
Lovastatin 40 mg	Lovastatin C_max ↑ 14.5 – >20 times, AUC ↑ > 14.8 – >20 times Lovastatin acid C_max ↑ 11.5–13 times, AUC ↑ 15.4–20 times	Contraindicated
Simvastatin 40 mg	Simvastatin acid C_max ↑ 17 times, AUC ↑ 19 times	Contraindicated
Atorvastatin	Atorvastatin acid C_max ↑ 2.5 times, AUC ↑ 40 % 3 times	Not recommended
Psychoanalepics; psycholeptics (e.g., antipsychotics, anxiolytics and hypnotics)
Lurasidone, pimozide, quetiapine, sertindole	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Midazolam (oral) 7.5 mg	Midazolam (oral) C_max ↑ 2.5–3.4 times, AUC ↑ 6.6–10.8 times	Contraindicated
Triazolam 0.25 mg	Triazolam C_max ↑, AUC ↑	Contraindicated
Alprazolam 0.8 mg	Alprazolam C_max ↔, AUC ↑ 2.8 times	Use with caution
Aripiprazole 3 mg	Aripiprazole C_max ↑ 19 %, AUC ↑ 48%	Use with caution
Brotizolam 0.5 mg	Brotizolam C_max ↔, AUC ↑ 2.6 times	Use with caution
Buspirone 10 mg	Buspirone C_max ↑ 13.4 times, AUC ↑ 19.2 times	Use with caution
Midazolam (IV) 7.5 mg	Midazolam concentration ↑ Itraconazole likely increases Midazolam concentrations for oral mucosal application (not directly studied)	Use with caution
Risperidone 2–8 mg/day	Concentration of Risperidone and active metabolite ↑	Use with caution
Zopiclone 7.5 mg	Zopiclone C_max ↑ 30 %, AUC ↑ 70 %	Use with caution
Cariprazine, galantamine, haloperidol, reboxetine, venlafaxine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Respiratory agents
Lumacaftor/ivacaftor 200/250 mg orally twice daily	Ivacaftor C_max ↑ 3.6 times, AUC ↑ 4.3 times Lumacaftor C_max ↔, AUC ↔	Not recommended
Ivacaftor	Itraconazole likely increases Ivacaftor concentrations (not directly studied)	Use with caution
Sex hormones and modulators of the genital system; other gynecological products
Cabergoline, dienogest, ulipristal	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Medications affecting the urinary system
Avanafil, dapoxetine, darifenacin	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Fezoterodine	Itraconazole likely increases the concentration of active metabolites, 5-hydroxymethyltolterodine (not directly studied)	Moderate or severe renal or hepatic impairment: contraindicated. Mild renal or hepatic impairment: concomitant use should be avoided. Normal renal and hepatic function: use with caution with a maximum dose of fezoterodine 4 mg
Solifenacin	Itraconazole likely increases Solifenacin concentrations (not directly studied)	Severe renal impairment: contraindicated. Moderate or severe hepatic impairment: contraindicated. Use with caution in all other patients with a maximum dose of solifenacin 5 mg.
Vardenafil	Itraconazole likely increases Vardenafil concentrations (not directly studied)	Contraindicated in patients over 75 years of age; not recommended in other patients.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Oxybutynine 5 mg	Oxybutynine C_max ↑ 2 times, AUC ↑ 2 times N-desethyl oxybutynine C_max ↔, AUC ↔ Itraconazole likely increases the concentration of oxybutynine after transdermal administration (not directly studied)	Use with caution
Other medicinal products and substances
Colchicine	Itraconazole likely increases Colchicine concentration (not directly studied)	Contraindicated for patients with impaired renal or hepatic function. Not recommended for other patients.
Eliglustat	Itraconazole likely increases Eliglustat concentration (not directly studied)	Contraindicated in CYP2D6 poor metabolizers (PM). Contraindicated in intermediate metabolizers (IM) or extensive metabolizers (EM) receiving a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IMs and EMs. For CYP2D6 EMs with mild hepatic impairment, a dose of Eliglustat 84 mg/day should be considered.
Synacalcet	Itraconazole likely increases Synacalcet concentration (not directly studied)	Use with caution

Precautions for use

Cross-hypersensitivity

There are no data on cross-hypersensitivity between itraconazole and other azole antifungal agents. Itraconazole should be used with caution in patients with hypersensitivity to other azoles.

Cardiac effects

Transient, asymptomatic decreases in left ventricular ejection fraction have been observed in studies of intravenous itraconazole in healthy volunteers. These changes were reversible before the next infusion. The clinical significance of this finding for oral formulations is unknown.

Itraconazole has been shown to have a negative inotropic effect. Cases of congestive heart failure (CHF) have been reported in association with itraconazole use. According to spontaneous reports, the incidence of congestive heart failure was higher at a total daily dose of 400 mg per day than at lower daily doses, so the risk of heart failure may increase depending on the total daily dose of itraconazole.

Itraconazole should not be used in patients with current or a history of congestive heart failure unless the potential benefit clearly outweighs the risk. When considering individual risk/benefit assessment, factors such as the severity of the underlying condition, dosing regimen, duration of treatment (total daily dose), and individual risk factors for CHF should be taken into account. These risk factors include cardiac disorders such as ischemic heart disease or valvular disease; severe pulmonary diseases such as chronic obstructive pulmonary disease; renal impairment or other conditions associated with oedema. Such patients should be informed of the signs and symptoms of congestive heart failure, and treatment should be carried out with caution and monitored for signs and symptoms of congestive heart failure. If such symptoms occur during treatment, itraconazole should be discontinued.

Calcium channel blockers can exhibit negative inotropic effects that may enhance the effect of itraconazole. In addition, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when itraconazole is used concomitantly with calcium channel blockers due to the increased risk of CHF (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic effects

Severe hepatotoxicity, including cases of fatal acute liver failure, has been reported rarely during itraconazole therapy. Most of these cases occurred in patients with pre-existing liver disease, systemic indications for treatment, comorbid serious illnesses and/or concomitant hepatotoxic drugs. However, some cases occurred in patients without obvious risk factors. Hepatotoxicity may occur within the first month of treatment, including during the first week. Monitoring of liver function is recommended in patients receiving itraconazole. Patients should be instructed to report any signs or symptoms of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. If such symptoms occur, treatment should be discontinued immediately and liver function testing performed.

There are limited data on the use of oral itraconazole in patients with hepatic impairment. The medicinal product should be used with caution in this population. Close monitoring is recommended in patients with hepatic dysfunction receiving itraconazole. When prescribing other medicinal products metabolised via CYP3A4, it is important to consider the prolonged half-life of itraconazole observed in clinical studies involving cirrhotic patients administered single doses of itraconazole capsules.

Itraconazole treatment is not recommended in patients with elevated liver enzymes, active liver disease, or a history of hepatotoxicity from other drugs unless the expected benefit clearly outweighs the potential risk. Liver function monitoring is advisable in patients with hepatic impairment or a history of drug-induced hepatotoxicity (see section “Pharmacokinetics”).

Reduced gastric acidity

Absorption of itraconazole is reduced in conditions of decreased gastric acidity. In patients with reduced gastric acidity due to disease (e.g., achlorhydria) or concomitant use of other drugs (e.g., to reduce gastric acidity), it is recommended to take the medicinal product with acidic beverages (e.g., non-diet cola). Antifungal efficacy should be monitored, and itraconazole dosage should be increased if necessary (see section “Interaction with other medicinal products and other forms of interaction”).

Paediatric population

The safety and efficacy of itraconazole in children (under 18 years of age) have not been established (see sections “Adverse reaction” and “Pharmacokinetics”).

Elderly

Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole should not be used in elderly patients unless the expected benefit outweighs the potential risk. Dose selection should be made cautiously, considering hepatic, renal, or cardiac function, as well as concomitant diseases and concomitant medicinal products.

Renal impairment

Data on the use of oral itraconazole in patients with renal impairment are limited. Oral bioavailability may be decreased in such patients. Caution is advised, and dose adjustment may be considered.

Hearing loss

Cases of transient or permanent hearing loss have been reported in patients receiving itraconazole. In some cases, hearing loss occurred during concomitant administration with quinidine, which is contraindicated (see sections “Contraindications” and “Interaction with other medicinal products and other forms of interaction”). Hearing usually returns after discontinuation of treatment; however, in some patients, hearing loss may be irreversible.

Immunocompromised patients

In certain immunocompromised patients (e.g., neutropenic patients, patients with AIDS, or organ transplant recipients), the oral bioavailability of itraconazole may be decreased.

Patients with life-threatening systemic fungal infections

Due to its pharmacokinetic properties (see section “Pharmacokinetics”), itraconazole is not recommended as the initial therapy for life-threatening systemic fungal infections.

Patients with AIDS

The need for maintenance therapy should be evaluated by the physician 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.

Neuropathy

If neuropathy occurs during itraconazole treatment, therapy should be discontinued.

Cystic fibrosis

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

Carbohydrate metabolism disorders

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product. If the patient has been told they have intolerance to some sugars, they should consult a doctor before taking this medicine.

Cross-resistance

In cases of systemic candidiasis, if there is a suspicion that the causative Candida species are resistant to fluconazole, susceptibility to itraconazole cannot be assumed. A sensitivity test should be conducted prior to initiating itraconazole treatment.

Interaction potential

Concomitant use of itraconazole with certain medicinal products may lead to changes in the efficacy of itraconazole and/or the co-administered medicinal product, occurrence of life-threatening adverse reactions, and/or sudden death. Medicinal products that are contraindicated or require caution when used with itraconazole are listed in section “Interaction with other medicinal products and other forms of interaction”.

Pregnancy and lactation

Pregnancy

Itraconazole should not be prescribed during pregnancy except in life-threatening situations, where the potential benefit to the pregnant woman outweighs the possible risk to the foetus (see section “Contraindications”).

Animal studies have shown reproductive toxicity of itraconazole.

Data on the use of itraconazole during pregnancy are limited. Cases of developmental anomalies have been reported, including malformations of the skeletal, genitourinary and cardiovascular systems, as well as of the eyes, in addition to chromosomal abnormalities and multiple congenital anomalies. A causal relationship with itraconazole has not been established.

Epidemiological data on the use of itraconazole during the first trimester of pregnancy (mainly in women treated short-term for vulvovaginal candidiasis) have not shown an increased risk of congenital malformations compared to the general population of women not exposed to teratogenic medicinal products.

Women of reproductive age

Women of reproductive age receiving itraconazole should use effective contraceptive measures throughout the course of treatment and until the onset of the first menstrual period after treatment has ended.

Breastfeeding

Only 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 itraconazole treatment for the mother. In cases of doubt, the woman should discontinue breastfeeding.

Fertility

In rats, itraconazole did not affect the fertility of males or females at doses associated with general toxicity (see section “Preclinical safety data”). The effect on human fertility is unknown.

Effects on ability to drive vehicles or other mechanisms.

No studies have been conducted on the effects of itraconazole on the ability to drive or use machines. However, patients should be aware of the possible occurrence of side effects such as dizziness, visual disturbances or hearing loss (see section “Adverse reactions”), which may impair the ability to drive vehicles or operate machinery.

Method of administration and dosage.

Itrungar capsules should be taken orally immediately after meals to ensure maximum absorption of the drug. The capsules should be swallowed whole.

Table 3

Treatment regimens for adults for each indication:

Indications for use	Dose	Duration	Remarks
• Vulvovaginal candidiasis	200 mg twice daily	1 day
• Pityriasis versicolor	200 mg once daily	7 days
• Tinea cruris, tinea corporis	100 mg once daily	15 days
• Tinea cruris, tinea corporis	200 mg once daily	7 days
• Tinea pedis, tinea manuum	100 mg once daily	30 days
• Oropharyngeal candidiasis	100 mg once daily	15 days	The dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS, due to impaired absorption of the medicinal product in these patients.
• Onychomycosis (toenail infections with or without fingernail involvement)	200 mg once daily	3 months
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 itraconazole is eliminated more slowly from skin, nail and mucous membrane tissues than from blood plasma.

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

Table 4

Systemic mycoses
Indications for use	Dosage¹	Remarks
Aspergillosis	200 mg once daily	Dose may be increased to 200 mg twice daily in cases of invasive or disseminated disease.
Candidiasis	100–200 mg once daily	Dose may be increased to 200 mg twice daily in cases of invasive or disseminated disease.
Cryptococcosis (without signs of meningitis)	200 mg once daily
Cryptococcal meningitis	200 mg twice daily	Maintenance therapy (see section “Precautions for use”).
Histoplasmosis	200 mg once daily up to 200 mg twice daily
Maintenance treatment in patients with AIDS	200 mg once daily	See remark regarding impaired absorption below.
Prophylaxis in patients with neutropenia	200 mg once daily	See remark regarding impaired absorption below.
¹ The duration of treatment should be adjusted depending on the clinical response. Malabsorption in patients with AIDS and neutropenia may lead to low blood concentrations of itraconazole and reduced efficacy. In such cases, it is recommended to monitor the level of itraconazole in the blood and, if necessary, increase the dose to 200 mg twice daily.

Elderly

Use of the medicinal product in elderly patients is not recommended (see section “Precautions for use”).

Patients with renal impairment

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

Patients with hepatic impairment

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

Children.

The safety and efficacy of itraconazole in children and adolescents (under 18 years of age) have not been established. The use of the medicinal product in children is not recommended.

Overdose.

In general, the adverse reactions reported in cases of overdose were similar in nature to those observed with normal use of itraconazole (see section “Adverse reactions”). In case of overdose, supportive measures should be implemented. Itraconazole cannot be removed by haemodialysis. There is no specific antidote. For the most recent recommendations on the management of overdose, contact a poison control centre.

Adverse reactions.

The adverse reactions listed below were reported during open-label and double-blind clinical trials involving 8,499 patients treated with itraconazole capsules for dermatomycoses or onychomycoses, as well as from post-marketing spontaneous reports.

The adverse reactions listed below are classified by organ system, and within each organ system, they are listed by frequency. The 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 infection, rhinitis.

Blood and lymphatic system disorders

Rare – leukopenia.

Immune system disorders

Uncommon – hypersensitivity*.

Rare – serum sickness, angioedema, anaphylactic reactions.

Metabolism and nutrition disorders

Rare – hypertriglyceridaemia.

Nervous system disorders

Common – headache.

Rare – paraesthesia, hypoaesthesia, dysgeusia, tremor.

Eye disorders

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

Ear and labyrinth disorders

Rare – transient or permanent hearing loss*, tinnitus.

Cardiac disorders

Rare – congestive heart failure*.

Respiratory, thoracic and mediastinal disorders

Rare – dyspnoea.

Gastrointestinal disorders

Common – abdominal pain, nausea.

Uncommon – diarrhoea, vomiting, constipation, dyspepsia, flatulence.

Rare – pancreatitis.

Hepatobiliary disorders

Uncommon – hepatic function disorder.

Rare – severe hepatotoxicity (including several cases of severe acute hepatic failure with a fatal outcome)*, hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

Uncommon – urticaria, rash, pruritus.

Rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.

Renal and urinary disorders

Rare – pollakiuria.

Reproductive system and breast disorders

Uncommon – menstrual disorders.

Rare – erectile dysfunction.

General disorders and administration site conditions

Uncommon – oedema.

Investigations

Rare – increased blood creatine phosphokinase.

* See section “Precautions for use”.

List of specific adverse reactions.

The following adverse reactions associated with the use of itraconazole have been reported in clinical studies of the oral solution and intravenous formulation, excluding injection site inflammation, as this reaction is specific only to the intravenous formulation.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

Metabolism and nutrition disorders: hyperglycaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia.

Psychiatric disorders: confusional state.

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

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

Vascular disorders: hypertension, hypotension.

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

Gastrointestinal disorders: gastrointestinal disturbances.

Hepatobiliary disorders: hepatic failure*, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary disorders: renal impairment, urinary incontinence.

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

Laboratory investigations: increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased alkaline phosphatase, increased lactate dehydrogenase (LDH), increased blood urea, increased gamma-glutamyltransferase (GGT), increased hepatic enzymes, abnormal urine test results.

Adverse Reactions Reporting

Adverse reactions reporting after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and cases of lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Packaging. 4 or 15 capsules in a blister. 1 blister in a cardboard box.

Terms of dispensing. On prescription.

Date of last update.

29.04.2024

INSTRUCTION

for medical use of the medicinal product

ITRUNGAR

Composition:

active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

excipients:

pellets contain: hydroxypropyl methylcellulose, corn starch, saccharose;

capsule coat contains:

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

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

Pharmaceutical form. Capsules.

Basic physical and chemical properties: hard gelatine capsules with a yellow body and green cap or vice versa (size 0); capsule contents – white to grey pellets.

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

Pharmacological properties.

Pharmacodynamics.

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

Fungi not inhibited by itraconazole include zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., Absidia spp.), Fusarium spp., Scedosporium proliferans, and Scopulariopsis spp.

Pharmacokinetics

General pharmacokinetic characteristics

Absorption

Plasma concentrations of itraconazole after capsule use are lower than those after equivalent oral solution doses (see section “Precautions for use”).

Distribution

Biotransformation

Elimination

Special patient populations

Hepatic impairment

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

Renal impairment

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 hydroxy-itraconazole.

Paediatric population

Clinical particulars

Indications

- Vulvovaginal candidiasis;
- Pityriasis versicolor;
- Dermatomycoses caused by itraconazole-sensitive 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 has proven ineffective 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 patients with AIDS to prevent relapse of existing fungal infections.

Itrungar is also indicated for the prevention of fungal infections in patients with prolonged neutropenia in cases where standard therapy is insufficient.

Contraindications

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

Analgesics; Anaesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Systemic antibacterials; antimycobacterial agents; systemic antifungals
Isavuconazole
Anthelmintics; Antiprotozoals
Halofantrine
Systemic antihistamines
Astemizole	Mizolastine	Terfenadine
Antineoplastic agents
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukaemia during initiation and dose titration phase)
Antiplatelet agents
Dabigatran	Ticagrelor
Systemic antivirals
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
Cardiovascular system (agents acting on the renin–angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiotherapy; diuretics)
Aliskiren	Eplerenone	Quinidine
Bepridil	Finerenone	Ranolazine
Disopyramide	Ivabradine	Sildenafil (for pulmonary hypertension)
Dofetilide	Lercanidipine
Dronedarone	Nisoldipine
Gastrointestinal medicines, including antidiarrheals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride	Domperidone	Naloxegol
Lipid-modifying agents
Lovastatin	Lomitapide	Simvastatin
Psychoanaleptics; psycholeptics (e.g. antipsychotics, anxiolytics and hypnotics)
Lurasidone	Pimozide	Sertindole
Oral midazolam	Quetiapine	Triazolam
Medicinal products affecting the urinary system
Avanafil	Darifenacin	Solifenacin (in patients with severe renal or moderate to severe hepatic impairment)
Dapoxetine	Fesoterodine (in patients with moderate or severe renal or hepatic impairment)	Vardenafil (in patients aged 75 years and older)
Other medicinal products and substances
Colchicine (in patients with renal or hepatic impairment)	Eliglustat (in patients who are CYP2D6 poor (PM), intermediate (IM), or extensive (EM) metabolizers taking a strong or moderate CYP2D6 inhibitor)

The medicinal product should not be used during pregnancy, except for the treatment of life-threatening conditions in the mother (see section "Pregnancy and lactation").

Women of childbearing potential must use effective contraception throughout the entire course of treatment with itraconazole and until completion of the menstrual cycle following the end of therapy.

Interaction with other medicinal products and other forms of interaction

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

Examples of medicinal products that may affect plasma concentrations of itraconazole are listed by pharmacological class in Table 1 below.

- "Contraindicated": the medicinal product must not be co-administered with itraconazole under any circumstances and for two weeks after discontinuation of itraconazole.
- "Not recommended": concomitant use and use within 2 weeks of discontinuing itraconazole should be avoided unless the benefit outweighs the potential risk of adverse effects. If concomitant use cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged pharmacological effects of the co-administered medicinal product is recommended, and its dose should be reduced or discontinued as necessary. Plasma concentrations of the co-administered drug may be monitored where appropriate.
- "Use with caution": close monitoring is recommended during concomitant use with itraconazole. Patients should be monitored carefully for signs or symptoms of increased or prolonged pharmacological effects of the co-administered medicinal product, and the dose should be reduced if necessary. Monitoring of plasma concentrations of the co-administered drug may be considered.

Table 1

Medicinal products that may affect plasma concentrations of itraconazole

Medicinal Products (oral single dose unless otherwise stated)

Expected/Potential Impact on Itraconazole Levels:

↑ increase

↔ no changes

↓ decrease

Clinical comment (see also the information above, as well as the sections “Contraindications” and “Precautions for use”)

Systemic antibacterials; antimycobacterial agents

Isoniazid

Likely decreases Itraconazole concentration (not directly studied)

Not recommended

Rifampicin 600 mg orally once daily

Itraconazole AUC ↓

Not recommended

Rifabutin 300 mg orally once daily

Itraconazole C_max ↓ 71 %, AUC ↓ 74 %

Not recommended

Ciprofloxacin 500 mg orally twice daily

Itraconazole C_max ↑ 53 %, AUC ↑ 82 %

Use with caution

Erythromycin 1 g

Itraconazole C_max ↑ 44 %, AUC ↑ 36 %

Use with caution

Clarithromycin 500 mg orally twice daily

Itraconazole C_max ↑ 90 %, AUC ↑ 92 %

Use with caution

Antiepileptic drugs

Carbamazepine, Phenobarbital

Likely decrease Itraconazole concentration (not directly studied)

Not recommended

Phenytoin 300 mg orally once daily

Itraconazole C_max ↓ 83 %, AUC ↓ 93 %

Hydroxy-itraconazole C_max ↓ 84 %, AUC ↓ 95 %

Not recommended

Antineoplastic drugs

Idelalisib

Likely increases Itraconazole concentration (not directly studied)

Use with caution

Systemic antivirals

Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)

Likely increase Itraconazole concentration (not directly studied)

Contraindicated

Efavirenz 600 mg

Itraconazole C_max ↓ 37 %, AUC ↓ 39 %

Hydroxy-itraconazole C_max ↓ 35 %, AUC ↓ 37 %

Not recommended

Nevirapine 200 mg orally once daily

Itraconazole C_max ↓ 38 %, AUC ↓ 62 %

Not recommended

Cobicistat, darunavir (boosted), elvitegravir (boosted with ritonavir), fosamprenavir (boosted with ritonavir), ritonavir, saquinavir (boosted with ritonavir)

Likely increase Itraconazole concentration (not directly studied)

Use with caution

Indinavir 800 mg orally three times daily

Itraconazole concentration ↑

Use with caution

Calcium channel blockers

Diltiazem

Likely increases Itraconazole concentration (not directly studied)

Use with caution

Medicines for treating disorders associated with increased or decreased acidity

Antacids (aluminium, calcium, magnesium or sodium bicarbonate), H₂ receptor antagonists (e.g. cimetidine, ranitidine), proton pump inhibitors (e.g. lansoprazole, omeprazole, rabeprazole)

Itraconazole C_max ↓, AUC ↓

Use with caution

Respiratory system drugs

Lumacaftor/ivacaftor 200/250 mg orally twice daily

Itraconazole concentration ↓

Not recommended

Other drugs and substances

St. John’s wort

(Hypericum perforatum)

Likely decreases itraconazole concentration (not directly studied)

Not recommended

Table 2.

Examples of drugs whose plasma concentrations may be affected by itraconazole

Medicinal Products (oral single dose unless otherwise stated)	Expected/Potential Impact on Itraconazole Levels: ↑ increase ↔ no changes ↓ decrease	Clinical comment (see also the information above, as well as the sections “Contraindications” and “Precautions for use”)
Analgesics; anesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Eletriptan, fentanyl	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Alfentanil, buprenorphine (IV and sublingual), cannabinoids, methadone, sufentanil	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Oxycodone 10 mg orally	Oxycodone orally C_max ↑ 45 %, AUC ↑ 2.4 times	Use with caution
Oxycodone 0.1 mg/kg IV	Oxycodone IV AUC ↑ 51 %	Use with caution
Systemic antibacterials; antimycobacterials; systemic antimycotics
Isavuconazole	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated
Bedaquiline	Itraconazole likely increases concentrations of this drug (not directly studied)	Not recommended
Rifabutin 300 mg orally once daily	Rifabutin concentration ↑ (volume unknown)	Not recommended
Clarithromycin 500 mg orally twice daily	Clarithromycin concentration ↑	Use with caution
Delamanid	Itraconazole likely increases concentrations of this drug (not directly studied)	Use with caution
Antiepileptic drugs
Carbamazepine	Itraconazole likely increases concentrations of this drug (not directly studied)	Not recommended
Anti-inflammatory and antirheumatic drugs
Meloxicam 15 mg	Meloxicam C_max ↓ 64 %, AUC ↓ 37 %	Use with caution
Anthelmintic; antiprotozoal drugs
Halofantrine	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated
Artemether-lumefantrine, praziquantel	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Quinine 300 mg	Quinine C_max ↔, AUC ↑ 96 %	Use with caution
Systemic antihistamines
Astemizole, mizolastine, terfenadine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Ebastine 20 mg	Ebastine C_max ↑ 2.5 times, AUC ↑ 6.2 times Carebastine C_max ↔, AUC ↑ 3.1 times	Not recommended
Bilastine, rupatadine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Antineoplastic drugs
Irinotecan	Itraconazole likely increases Irinotecan and active metabolite levels (not directly studied)	Contraindicated
Venetoclax	Itraconazole likely increases concentrations of this drug (not directly studied)	Contraindicated in patients with chronic lymphocytic leukaemia during dose initiation and titration. Otherwise, not recommended unless the benefits outweigh the risks. Refer to venetoclax prescribing information.
Axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, crizotinib, dabrafenib, dasatinib, docetaxel, everolimus, glasdegib, ibrutinib, lapatinib, nilotinib, pazopanib, regorafenib, sunitinib, temsirolimus, trabectedin, trastuzumab, emtansine, vinca alkaloids (e.g., vinflunine, vinorelbine)	Itraconazole likely increases concentrations of these drugs (not directly studied), with the exception of Cabazitaxel and Regorafenib. There are no statistically significant changes in Cabazitaxel exposure, but there is considerable variability in the results. The AUC of Regorafenib is expected to decrease (based on the active fraction).	Not recommended
Cobimetinib 10 mg	Cobimetinib C_max ↑ 3.2 times, AUC ↑ 6.7 times	Not recommended
Entrectinib	Entrectinib C_max ↑73 %, AUC ↑ 6.0 times	Not recommended
Olaparib 100 mg	Olaparib C_max ↑ 40 %, AUC ↑ 2.7 times	Not recommended
Talazoparib	Talazoparib C_max ↑ 40 %, AUC ↑ 56 %	Not recommended
Alitretinoin (oral), bortezomib, brentuximab vedotin, erlotinib, idelalisib, imatinib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, tretinoin (oral)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Busulfan 1 mg/kg every 6 hours	Busulfan C_max ↑, AUC ↑	Use with caution
Gefitinib 250 mg	Gefitinib 250 mg C_max ↑, AUC ↑ 78 %	Use with caution
Pemigatinib	Pemigatinib C_max ↑ 17 %, AUC ↑ 91 %	Use with caution
Antiplatelet drugs
Dabigatran, ticagrelor	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Cilostazol, coumarins (e.g. warfarin)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Antiviral drugs for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase paritaprevir concentration	Contraindicated
Elbasvir/grazoprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Cobicistat, elvitegravir (boosted with ritonavir), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Indinavir 800 mg orally 3 times a day	Indinavir C_max ↔, AUC ↑	Use with caution
Cardiovascular system (agents affecting the renin-angiotensin system; antihypertensive drugs; beta-blockers; calcium channel blockers; cardiac therapy; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, finerenone, ivabradine, lerkanidipine, nisoldipine, ranolazine, sildenafil (pulmonary hypertension)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Aliskiren 150 mg	Aliskiren C_max ↑ 5.8 times, AUC ↑ 6.5 times	Contraindicated
Quinidine 100 mg	Quinidine C_max ↑ 59 %, AUC ↑ 2.4 times	Contraindicated
Felodipine 5 mg	Felodipine C_max ↑ 7.8 times, AUC ↑ 6.3 times	Not recommended
Riociguat, tadalafil (pulmonary hypertension)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (e.g., amlodipine, isradipine, nifedipine, nimodipine), verapamil	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Digoxin 0.5 mg	Digoxin C_max ↑ 34 %, AUC ↑ 68 %	Use with caution
Nadolol 30 mg	Nadolol C_max ↑ 4.7 times, AUC ↑ 2.2 times	Use with caution
Corticosteroids for systemic use; drugs for obstructive airway diseases
Ciclesonide, salmeterol	Itraconazole likely increases concentrations of Salmeterol and the active metabolite of Ciclesonide (not directly studied)	Not recommended
Budesonide inhalation 1 mg single dose	Budesonide inhalation C_max ↑ 65 %, AUC ↑ 4.2 times Budesonide (other forms) concentration ↑	Use with caution
Dexamethasone IV 5 mg Dexamethasone oral 4.5 mg	Dexamethasone IV: C_max ↔, AUC ↑ 3.3 times Dexamethasone oral: C_max ↑ 69 %, AUC ↑ 3.7 times	Use with caution
Fluticasone inhalation 1 mg twice daily	Fluticasone concentration ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone oral C_max ↑ 92 %, AUC ↑ 3.9 times Methylprednisolone IV AUC ↑ 2.6 times	Use with caution
Fluticasone nasal	Itraconazole likely increases concentrations of intranasally administered Fluticasone (not directly studied)	Use with caution
Medications for diabetes mellitus
Repaglinide 0.25 mg	Repaglinide C_max ↑ 47 %, AUC ↑ 41 %	Use with caution
Saxagliptin	Itraconazole likely increases Saxagliptin concentrations (not directly studied)	Use with caution
Gastrointestinal agents, including antidiarrheals, intestinal anti-inflammatory/anti-infective drugs; antiemetics and anti-nausea drugs; laxatives; drugs for functional gastrointestinal disorders
Cisapride, naloxegol	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Domperidone 20 mg	Domperidone C_max ↑ 2.7 times, AUC ↑ 3.2 times	Contraindicated
Aprepitant, loperamide, netupitant	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Itraconazole likely increases Sirolimus concentrations (not directly studied)	Not recommended
Cyclosporine, tacrolimus	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Tacrolimus IV 0.03 mg/kg once daily	Tacrolimus IV concentration ↑	Use with caution
Lipid-regulating agents
Lomitapide	Itraconazole likely increases Lomitapide concentrations (not directly studied)	Contraindicated
Lovastatin 40 mg	Lovastatin C_max ↑ 14.5 – >20 times, AUC ↑ > 14.8 – >20 times Lovastatin acid C_max ↑ 11.5–13 times, AUC ↑ 15.4–20 times	Contraindicated
Simvastatin 40 mg	Simvastatin acid C_max ↑ 17 times, AUC ↑ 19 times	Contraindicated
Atorvastatin	Atorvastatin acid C_max ↑ 2.5 times, AUC ↑ 40 % 3 times	Not recommended
Psychoanalepics; psycholeptics (e.g., antipsychotics, anxiolytics and hypnotics)
Lurasidone, pimozide, quetiapine, sertindole	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Midazolam (oral) 7.5 mg	Midazolam (oral) C_max ↑ 2.5–3.4 times, AUC ↑ 6.6–10.8 times	Contraindicated
Triazolam 0.25 mg	Triazolam C_max ↑, AUC ↑	Contraindicated
Alprazolam 0.8 mg	Alprazolam C_max ↔, AUC ↑ 2.8 times	Use with caution
Aripiprazole 3 mg	Aripiprazole C_max ↑ 19 %, AUC ↑ 48%	Use with caution
Brotizolam 0.5 mg	Brotizolam C_max ↔, AUC ↑ 2.6 times	Use with caution
Buspirone 10 mg	Buspirone C_max ↑ 13.4 times, AUC ↑ 19.2 times	Use with caution
Midazolam (IV) 7.5 mg	Midazolam concentration ↑ Itraconazole likely increases Midazolam concentrations for oral mucosal application (not directly studied)	Use with caution
Risperidone 2–8 mg/day	Concentration of Risperidone and active metabolite ↑	Use with caution
Zopiclone 7.5 mg	Zopiclone C_max ↑ 30 %, AUC ↑ 70 %	Use with caution
Cariprazine, galantamine, haloperidol, reboxetine, venlafaxine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Respiratory agents
Lumacaftor/ivacaftor 200/250 mg orally twice daily	Ivacaftor C_max ↑ 3.6 times, AUC ↑ 4.3 times Lumacaftor C_max ↔, AUC ↔	Not recommended
Ivacaftor	Itraconazole likely increases Ivacaftor concentrations (not directly studied)	Use with caution
Sex hormones and modulators of the genital system; other gynecological products
Cabergoline, dienogest, ulipristal	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Medications affecting the urinary system
Avanafil, dapoxetine, darifenacin	Itraconazole likely increases concentrations of these drugs (not directly studied)	Contraindicated
Fezoterodine	Itraconazole likely increases the concentration of active metabolites, 5-hydroxymethyltolterodine (not directly studied)	Moderate or severe renal or hepatic impairment: contraindicated. Mild renal or hepatic impairment: concomitant use should be avoided. Normal renal and hepatic function: use with caution with a maximum dose of fezoterodine 4 mg
Solifenacin	Itraconazole likely increases Solifenacin concentrations (not directly studied)	Severe renal impairment: contraindicated. Moderate or severe hepatic impairment: contraindicated. Use with caution in all other patients with a maximum dose of solifenacin 5 mg.
Vardenafil	Itraconazole likely increases Vardenafil concentrations (not directly studied)	Contraindicated in patients over 75 years of age; not recommended in other patients.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Itraconazole likely increases concentrations of these drugs (not directly studied)	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Itraconazole likely increases concentrations of these drugs (not directly studied)	Use with caution
Oxybutynine 5 mg	Oxybutynine C_max ↑ 2 times, AUC ↑ 2 times N-desethyl oxybutynine C_max ↔, AUC ↔ Itraconazole likely increases the concentration of oxybutynine after transdermal administration (not directly studied)	Use with caution
Other medicinal products and substances
Colchicine	Itraconazole likely increases Colchicine concentration (not directly studied)	Contraindicated for patients with impaired renal or hepatic function. Not recommended for other patients.
Eliglustat	Itraconazole likely increases Eliglustat concentration (not directly studied)	Contraindicated in CYP2D6 poor metabolizers (PM). Contraindicated in intermediate metabolizers (IM) or extensive metabolizers (EM) receiving a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IMs and EMs. For CYP2D6 EMs with mild hepatic impairment, a dose of Eliglustat 84 mg/day should be considered.
Synacalcet	Itraconazole likely increases Synacalcet concentration (not directly studied)	Use with caution

Precautions for use

Cross-hypersensitivity

There are no data on cross-hypersensitivity between itraconazole and other azole antifungal agents. Itraconazole should be used with caution in patients with hypersensitivity to other azoles.

Cardiac effects

Hepatic effects

Reduced gastric acidity

Paediatric population

The safety and efficacy of itraconazole in children (under 18 years of age) have not been established (see sections “Adverse reaction” and “Pharmacokinetics”).

Elderly

Renal impairment

Data on the use of oral itraconazole in patients with renal impairment are limited. Oral bioavailability may be decreased in such patients. Caution is advised, and dose adjustment may be considered.

Hearing loss

Immunocompromised patients

In certain immunocompromised patients (e.g., neutropenic patients, patients with AIDS, or organ transplant recipients), the oral bioavailability of itraconazole may be decreased.

Patients with life-threatening systemic fungal infections

Due to its pharmacokinetic properties (see section “Pharmacokinetics”), itraconazole is not recommended as the initial therapy for life-threatening systemic fungal infections.

Patients with AIDS

Neuropathy

If neuropathy occurs during itraconazole treatment, therapy should be discontinued.

Cystic fibrosis

Carbohydrate metabolism disorders

Cross-resistance

Interaction potential

Pregnancy and lactation

Pregnancy

Animal studies have shown reproductive toxicity of itraconazole.

Women of reproductive age

Breastfeeding

Fertility

In rats, itraconazole did not affect the fertility of males or females at doses associated with general toxicity (see section “Preclinical safety data”). The effect on human fertility is unknown.

Effects on ability to drive vehicles or other mechanisms.

Method of administration and dosage.

Itrungar capsules should be taken orally immediately after meals to ensure maximum absorption of the drug. The capsules should be swallowed whole.

Table 3

Treatment regimens for adults for each indication:

Indications for use	Dose	Duration	Remarks
• Vulvovaginal candidiasis	200 mg twice daily	1 day
• Pityriasis versicolor	200 mg once daily	7 days
• Tinea cruris, tinea corporis	100 mg once daily	15 days
• Tinea cruris, tinea corporis	200 mg once daily	7 days
• Tinea pedis, tinea manuum	100 mg once daily	30 days
• Oropharyngeal candidiasis	100 mg once daily	15 days	The dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS, due to impaired absorption of the medicinal product in these patients.
• Onychomycosis (toenail infections with or without fingernail involvement)	200 mg once daily	3 months
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 itraconazole is eliminated more slowly from skin, nail and mucous membrane tissues than from blood plasma.

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

Table 4

Systemic mycoses
Indications for use	Dosage¹	Remarks
Aspergillosis	200 mg once daily	Dose may be increased to 200 mg twice daily in cases of invasive or disseminated disease.
Candidiasis	100–200 mg once daily	Dose may be increased to 200 mg twice daily in cases of invasive or disseminated disease.
Cryptococcosis (without signs of meningitis)	200 mg once daily
Cryptococcal meningitis	200 mg twice daily	Maintenance therapy (see section “Precautions for use”).
Histoplasmosis	200 mg once daily up to 200 mg twice daily
Maintenance treatment in patients with AIDS	200 mg once daily	See remark regarding impaired absorption below.
Prophylaxis in patients with neutropenia	200 mg once daily	See remark regarding impaired absorption below.
¹ The duration of treatment should be adjusted depending on the clinical response. Malabsorption in patients with AIDS and neutropenia may lead to low blood concentrations of itraconazole and reduced efficacy. In such cases, it is recommended to monitor the level of itraconazole in the blood and, if necessary, increase the dose to 200 mg twice daily.

Elderly

Use of the medicinal product in elderly patients is not recommended (see section “Precautions for use”).

Patients with renal impairment

Patients with hepatic impairment

Children.

The safety and efficacy of itraconazole in children and adolescents (under 18 years of age) have not been established. The use of the medicinal product in children is not recommended.

Overdose.

Adverse reactions.

Infections and infestations:

Uncommon – sinusitis, upper respiratory tract infection, rhinitis.

Blood and lymphatic system disorders

Rare – leukopenia.

Immune system disorders

Uncommon – hypersensitivity*.

Rare – serum sickness, angioedema, anaphylactic reactions.

Metabolism and nutrition disorders

Rare – hypertriglyceridaemia.

Nervous system disorders

Common – headache.

Rare – paraesthesia, hypoaesthesia, dysgeusia, tremor.

Eye disorders

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

Ear and labyrinth disorders

Rare – transient or permanent hearing loss*, tinnitus.

Cardiac disorders

Rare – congestive heart failure*.

Respiratory, thoracic and mediastinal disorders

Rare – dyspnoea.

Gastrointestinal disorders

Common – abdominal pain, nausea.

Uncommon – diarrhoea, vomiting, constipation, dyspepsia, flatulence.

Rare – pancreatitis.

Hepatobiliary disorders

Uncommon – hepatic function disorder.

Rare – severe hepatotoxicity (including several cases of severe acute hepatic failure with a fatal outcome)*, hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

Uncommon – urticaria, rash, pruritus.

Renal and urinary disorders

Rare – pollakiuria.

Reproductive system and breast disorders

Uncommon – menstrual disorders.

Rare – erectile dysfunction.

General disorders and administration site conditions

Uncommon – oedema.

Investigations

Rare – increased blood creatine phosphokinase.

* See section “Precautions for use”.

List of specific adverse reactions.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

Metabolism and nutrition disorders: hyperglycaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia.

Psychiatric disorders: confusional state.

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

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

Vascular disorders: hypertension, hypotension.

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

Gastrointestinal disorders: gastrointestinal disturbances.

Hepatobiliary disorders: hepatic failure*, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary disorders: renal impairment, urinary incontinence.

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

Adverse Reactions Reporting

Shelf life. 2 years.

Storage conditions.

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

Packaging. 4 or 15 capsules in a blister. 1 blister in a cardboard box.

Terms of dispensing. On prescription.

Date of last update.

29.04.2024