Itrungar: detailed information

INSTRUCTION FOR MEDICINAL USE OF THE MEDICINAL PRODUCT ITROUNGAR (ITRUNGAR)

Composition:

Active substance: itraconazole;

1 capsule contains itraconazole 100 mg;

Excipients:

pellets contain: hydroxypropylmethylcellulose, maize starch, sucrose;

capsule shell contains:

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

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

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules with yellow body and green cap or vice versa (size 0); capsule contents – pellets ranging from white to grey.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole and tetrazole 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 were not defined according to EUCAST methodology. CLSI breakpoint values are: susceptible ≤0.125 μg/mL, dose-dependent susceptible 0.25–0.5 μg/mL, 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 fungi pathogenic to humans at concentrations generally ≤1 μg/mL. These include dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis, and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.), Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis; Pseudallescheria boydii; Penicillium marneffei; and other yeast and fungal species.

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

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

Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. Described mechanisms include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of efflux transporters resulting in increased export of itraconazole from fungal cells (thus removing itraconazole from its target site). Cross-resistance among azole-class drugs has been observed within Candida species; however, resistance to one azole does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics

General Pharmacokinetic Characteristics

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 administration of 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal half-life of itraconazole ranges from 16 to 28 hours after a single dose and increases to 34–42 hours after multiple doses. After discontinuation of treatment, itraconazole concentrations decline to nearly undetectable levels in plasma within 7–14 days, depending on dose and duration of therapy. The average plasma clearance of itraconazole after intravenous administration is 278 mL/min. Due to saturable hepatic metabolism, clearance of itraconazole decreases at higher doses.

Absorption

Itraconazole is rapidly absorbed after oral administration. Maximum plasma concentration of unchanged drug after oral capsule administration is reached within 2–5 hours. 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 decreased 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 is increased if Itrungar capsules are taken with acidic beverages (e.g., non-diet cola). After administration of a single 200 mg dose of Itrungar on an empty stomach with non-diet cola following ranitidine (an H2-receptor antagonist), absorption of itraconazole was comparable to that after administration of Itrungar 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

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

Biotransformation

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

Elimination

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

Special Patient Populations

Hepatic Impairment

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

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

Renal Impairment

Data on the use of oral itraconazole in patients with renal impairment are limited. A pharmacokinetic study using a single 200 mg dose of itraconazole (4 capsules of 50 mg) was conducted in 3 groups of patients with renal dysfunction (uremia: n=7, hemodialysis: n=7, 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 compared to 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 across all 3 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, respectively). Total itraconazole concentrations based on AUC were reduced by 30% and 40%, respectively, in patients with moderate and severe renal impairment compared to healthy volunteers.

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

Pediatric Population

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

Clinical characteristics.

Indications.

Vulvovaginal candidiasis;
pityriasis versicolor;
dermatomycoses caused by itraconazole-susceptible pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), for example, tinea pedis, tinea cruris, tinea corporis, tinea manuum;
oropharyngeal candidiasis;
onychomycoses caused by dermatophytes and/or yeasts;
histoplasmosis;
systemic mycoses (in cases where first-line antifungal therapy cannot be used or when treatment with other antifungal agents is ineffective, which may be due to underlying disease, pathogen resistance, or drug toxicity):
aspergillosis and candidiasis;
cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with central nervous system cryptococcosis;
maintenance therapy in AIDS patients to prevent recurrence of existing fungal infection.

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

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 types of interactions» and «Special precautions for use»). These include:

Analgesics; anesthetics
Alkaloids of ergot (e.g., dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Antibacterials for systemic use; antimycobacterials; antifungals for systemic use
Isavuconazole
Antihelminthics; antiprotozoals
Halofantrine
Antihistamines for systemic use
Astemizole	Mizolastine	Terfenadine
Antineoplastics
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukemia during the initiation and dose-titration phase of venetoclax)
Antithrombotics
Dabigatran	Ticagrelor
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiologic therapy; diuretics)
Aliskiren	Eplerenone	Quinidine
Bepridil	Finerenone	Ranolazine
Disopyramide	Ivabradine	Sildenafil (pulmonary hypertension)
Dofetilide	Lercanidipine
Dronedarone	Nisoldipine
Gastrointestinal agents, 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
Midazolam (oral)	Quetiapine	Triazolam
Agents affecting the urinary system
Avanafil	Darifenacin	Solifenacin (in patients with severe renal impairment or moderate to severe hepatic impairment)
Dapoxetine	Fesoterodine (in patients with moderate or severe renal or hepatic impairment)	Vardenafil (in patients aged 75 years)
Other medicinal products and substances
Colchicine (in patients with renal or hepatic impairment)	Eliglustat (in patients who are poor metabolizers (PM), intermediate metabolizers (IM), or rapid metabolizers (RM) of CYP2D6 and who are taking a strong or moderate inhibitor of CYP2D6)

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

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

Women of childbearing potential should use reliable contraceptive methods during the entire course of treatment with itraconazole and throughout the menstrual cycle after completion of treatment.

Interaction with other medicinal products and other forms of interaction.

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

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

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

Examples of drugs whose plasma concentrations may be affected by itraconazole are listed in Table 2 below. Potential changes in safety or efficacy of interacting drugs are not considered. For additional information, refer to the relevant product information for the medicinal product.

Combinations of itraconazole with drugs described in Tables 1 and 2 are classified as contraindicated, not recommended, or to be used with caution, depending on the degree of increase in concentration and the safety profile of the interacting drug (see also sections "Contraindications" and "Special precautions"). The interaction potential of the listed drugs was assessed based on pharmacokinetic study data of itraconazole or other strong CYP3A4 inhibitors (e.g., ketoconazole) in humans and/or in vitro data:

"Contraindicated": The drug must not be used concomitantly with itraconazole and for two weeks after discontinuation of itraconazole treatment under any circumstances.
"Not recommended": Concomitant use of these medicinal products and for two 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, clinical monitoring for signs or symptoms of increased or prolonged pharmacological effect of the co-administered drug is recommended, and its dose should be reduced or discontinued if necessary. If needed, measurement of plasma concentration of the co-administered drug is recommended.
"Use with caution": Careful monitoring is recommended when used concomitantly with itraconazole. Close observation of patients for signs or symptoms of increased or prolonged pharmacological effect of the co-administered drug is recommended during concomitant use, and dose reduction may be necessary. If needed, measurement of plasma concentration of the co-administered drug is recommended.

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

After discontinuation of treatment, itraconazole plasma concentrations decrease to the limit of quantification within 7–14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in patients concurrently using CYP3A4 inhibitors, the decline in plasma concentration may be more gradual. This is particularly relevant for drugs whose metabolism is affected by itraconazole (see section "Pharmacokinetics").

Table 1.

Drugs that may affect itraconazole plasma concentrations

Medicinal products (oral single dose unless otherwise stated) within class	Expected/potential effect on itraconazole levels: ↑ increase ↔ no change ↓ decrease	Clinical comment (see additional information above, as well as sections "Contraindications" and "Special precautions")
Antibacterials for systemic use; antimycobacterials
Isoniazid	Although isoniazid has not been studied directly, it is likely to reduce itraconazole concentration	Not recommended
Rifampicin oral 600 mg once daily	Itaconazole AUC ↓	Not recommended
Rifabutin oral 300 mg once daily	Itaconazole Cmax ↓ 71%, AUC ↓ 74%	Not recommended
Ciprofloxacin oral 500 mg twice daily	Itaconazole Cmax ↑ 53%, AUC ↑ 82%	Use with caution
Erythromycin 1 g	Itaconazole Cmax ↑ 44%, AUC ↑ 36%	Use with caution
Clarithromycin oral 500 mg twice daily	Itaconazole Cmax ↑ 90%, AUC ↑ 92%	Use with caution
Antiepileptic drugs
Carbamazepine, phenobarbital	Although these drugs have not been studied directly, they are likely to reduce itraconazole concentration	Not recommended
Phenytoin oral 300 mg once daily	Itaconazole Cmax ↓ 83%, AUC ↓ 93% Hydroxyitraconazole Cmax ↓ 84%, AUC ↓ 95%	Not recommended
Antineoplastic agents
Idelalisib	Although idelalisib has not been studied directly, it is likely to increase itraconazole concentration	Use with caution
Systemic antiviral agents
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Although these agents have not been studied directly, an increase in itraconazole concentration is expected	Contraindicated
Efavirenz 600 mg	Itaconazole Cmax ↓ 37%, AUC ↓ 39% Hydroxyitraconazole Cmax ↓ 35%, AUC ↓ 37%	Not recommended
Nevaripine oral 200 mg once daily	Itaconazole Cmax ↓ 38%, AUC ↓ 62%	Not recommended
Cobicistat, darunavir (boosted), elvitegravir (ritonavir-boosted), fosamprenavir (ritonavir-boosted), ritonavir, saquinavir (ritonavir-boosted)	Although these agents have not been studied directly, an increase in itraconazole concentration is expected	Use with caution
Indinavir oral 800 mg three times daily	Itaconazole concentration ↑	Use with caution
Calcium channel blockers
Diltiazem	Although diltiazem has not been studied directly, it may increase itraconazole concentration	Use with caution
Agents for treatment of disorders related to increased or decreased acidity
Antacids (aluminum, calcium, magnesium or sodium bicarbonate), H2-receptor antagonists (e.g., cimetidine, ranitidine), proton pump inhibitors (e.g., lansoprazole, omeprazole, rabepazole)	Itaconazole Cmax ↓, AUC ↓	Use with caution
Agents affecting the respiratory system
Lumacaftor/ivacaftor oral 200/250 mg twice daily	Itaconazole concentration ↓	Not recommended
Other medicinal products and substances
St. John's wort (Hypericum perforatum)	Although St. John's wort has not been studied directly, it is likely to reduce itraconazole concentration	Not recommended

Table 2.

Examples of drugs whose plasma concentration may be affected by itraconazole

Medicinal products (oral single dose unless otherwise stated) within the class	Expected/potential effect on itraconazole levels: ↑ increase ↔ no change ↓ decrease	Clinical comment (see additional information above, as well as sections "Contraindications" and "Special precautions for use")
Analgesics; anaesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Although itraconazole has not been studied directly, it may increase the concentration of these drugs	Contraindicated
Eletriptan, fentanyl	Although itraconazole has not been studied directly, it may increase the concentration of these drugs	Not recommended
Alfentanil, buprenorphine (intravenous [i.v.] and sublingual), cannabinoids, methadone, sufentanil	Although itraconazole has not been studied directly, it may increase the concentration of these drugs	Use with caution
Oxycodone orally 10 mg	Oxycodone oral Cmax ↑ 45%, AUC ↑ 2.4-fold	Use with caution
Oxycodone i.v. 0.1 mg/kg	Oxycodone i.v. AUC ↑ 51%	Use with caution
Systemic antibacterials; antimycobacterials; systemic antifungals
Isavuconazole	Although itraconazole has not been studied directly, it may increase isavuconazole concentration	Contraindicated
Bedaquiline	Although itraconazole has not been studied directly, it may increase bedaquiline concentration	Not recommended
Rifabutin orally 300 mg once daily	Rifabutin concentration ↑ (extent unknown)	Not recommended
Clarithromycin orally 500 mg twice daily	Clarithromycin concentration ↑	Use with caution
Delamanid	Although itraconazole has not been studied directly, it may increase delamanid concentration	Use with caution
Antiepileptics
Carbamazepine	Although itraconazole has not been studied directly, it may increase carbamazepine concentration	Not recommended
Anti-inflammatory and antirheumatic agents
Meloxicam 15 mg	Meloxicam Cmax ↓ 64%, AUC ↓ 37%	Use with caution
Antihelminthics; antiprotozoals
Halofantrine	Although itraconazole has not been studied directly, it may increase halofantrine concentration	Contraindicated
Artemether-lumefantrine, praziquantel	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Quinine 300 mg	Quinine Cmax ↔, AUC ↑ 96%	Use with caution
Systemic antihistamines
Astemizole, mizolastine, terfenadine	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Ebastine 20 mg	Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2-fold Carbastine Cmax ↔, AUC ↑ 3.1-fold	Not recommended
Bilastine, rupatadine	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Antineoplastics
Irinotecan	Although itraconazole has not been studied directly, it may increase irinotecan and its active metabolite concentration	Contraindicated
Venetoclax	Although itraconazole has not been studied directly, it may increase venetoclax concentration	Contraindicated in patients with chronic lymphocytic leukaemia at initiation and during the dose-titration phase of venetoclax. Otherwise not recommended unless benefits outweigh 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)	Although itraconazole has not been studied directly, it is likely to increase concentrations of these drugs, except for cabazitaxel and regorafenib. No statistically significant changes in cabazitaxel exposure, but high variability observed. AUC of regorafenib is expected to decrease (based on active moiety)	Not recommended
Cobimetinib 10 mg	Cobimetinib Cmax ↑ 3.2-fold, AUC ↑ 6.7-fold	Not recommended
Entrectinib	Entrectinib Cmax ↑ 73%, AUC ↑ 6.0-fold	Not recommended
Olapanib 100 mg	Olapanib Cmax ↑ 40%, AUC ↑ 2.7-fold	Not recommended
Talazoparib	Talazoparib Cmax ↑ 40%, AUC ↑ 56%	Not recommended
Alitretinoin (oral), bortezomib, brentuximab vedotin, erlotinib, idelalisib, imatinib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, trastuzumab emtansine, tretinoin (oral)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Busulfan 1 mg/kg every 6 hours	Busulfan Cmax ↑, AUC ↑	Use with caution
Gefitinib 250 mg	Gefitinib 250 mg Cmax ↑, AUC ↑ 78%	Use with caution
Pemigatinib	Pemigatinib Cmax ↑ 17%, AUC ↑ 91%	Use with caution
Antiplatelet agents
Dabigatran, ticagrelor	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Not recommended
Cilostazol, coumarins (e.g. warfarin)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Systemic antivirals
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase paritaprevir concentration	Contraindicated
Elbasvir/grazoprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Not recommended
Cobicistat, elvitegravir (boosted with ritonavir), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Indinavir orally 800 mg three times daily	Indinavir Cmax ↔, AUC ↑	Use with caution
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiac therapy; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, finerenone, ivabradine, lercanidipine, nisoldipine, ranolazine, sildenafil (pulmonary hypertension)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Aliskiren 150 mg	Aliskiren Cmax ↑ 5.8-fold, AUC ↑ 6.5-fold	Contraindicated
Quinidine 100 mg	Quinidine Cmax ↑ 59%, AUC ↑ 2.4-fold	Contraindicated
Felodipine 5 mg	Felodipine Cmax ↑ 7.8-fold, AUC ↑ 6.3-fold	Not recommended
Riociguat, tadalafil (pulmonary hypertension)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (e.g. amlodipine, isradipine, nifedipine, nimodipine), verapamil	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Digoxin 0.5 mg	Digoxin Cmax ↑ 34%, AUC ↑ 68%	Use with caution
Nadolol 30 mg	Nadolol Cmax ↑ 4.7-fold, AUC ↑ 2.2-fold	Use with caution
Systemic corticosteroids; agents for obstructive respiratory diseases
Ciclesonide, salmeterol	Although itraconazole has not been studied directly, it may increase salmeterol and active metabolite of ciclesonide concentrations	Not recommended
Budesonide inhaled 1 mg single dose	Budesonide inhaled Cmax ↑ 65%, AUC ↑ 4.2-fold Budesonide (other forms) concentration ↑	Use with caution
Dexamethasone i.v. 5 mg Dexamethasone orally 4.5 mg	Dexamethasone i.v.: Cmax ↔, AUC ↑ 3.3-fold Dexamethasone orally: Cmax ↑ 69%, AUC ↑ 3.7-fold	Use with caution
Fluticasone inhaled 1 mg twice daily	Fluticasone concentration ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone oral Cmax ↑ 92%, AUC ↑ 3.9-fold Methylprednisolone i.v. AUC ↑ 2.6-fold	Use with caution
Fluticasone nasal	Although itraconazole has not been studied directly, it is likely to increase intranasally administered fluticasone concentration	Use with caution
Antidiabetics
Repaglinide 0.25 mg	Repaglinide Cmax ↑ 47%, AUC ↑ 41%	Use with caution
Saxagliptin	Although itraconazole has not been studied directly, it may increase saxagliptin concentration	Use with caution
Gastrointestinal agents, including antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride, naloxegol	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Domperidone 20 mg	Domperidone Cmax ↑ 2.7-fold, AUC ↑ 3.2-fold	Contraindicated
Aprepitant, loperamide, netupitant	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Although itraconazole has not been studied directly, it may increase sirolimus concentrations	Not recommended
Cyclosporine, tacrolimus	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Tacrolimus i.v. 0.03 mg/kg once daily	Tacrolimus i.v. concentration ↑	Use with caution
Lipid-regulating drugs
Lomitapide	Although itraconazole has not been studied directly, it may increase lomitapide concentrations	Contraindicated
Lovastatin 40 mg	Lovastatin Cmax ↑ 14.5 – >20-fold, AUC ↑ >14.8 – >20-fold Lovastatin acid Cmax ↑ 11.5–13-fold, AUC ↑ 15.4–20-fold	Contraindicated
Simvastatin 40 mg	Simvastatin acid Cmax ↑ 17-fold, AUC ↑ 19-fold	Contraindicated
Atorvastatin	Atorvastatin acid Cmax ↑ up to 2.5-fold, AUC ↑ from 40% to 3-fold	Not recommended
Psychoanaleptics; psycholeptics (e.g. antipsychotics, anxiolytics and hypnotics)
Lurasidone, pimozide, quetiapine, sertindole	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Midazolam (oral) 7.5 mg	Midazolam (oral) Cmax ↑ 2.5–3.4-fold, AUC ↑ 6.6–10.8-fold	Contraindicated
Triazolam 0.25 mg	Triazolam Cmax ↑, AUC ↑	Contraindicated
Alprazolam 0.8 mg	Alprazolam Cmax ↔, AUC ↑ 2.8-fold	Use with caution
Aripiprazole 3 mg	Aripiprazole Cmax ↑ 19%, AUC ↑ 48%	Use with caution
Brothizolam 0.5 mg	Brothizolam Cmax ↔, AUC ↑ 2.6-fold	Use with caution
Buspirone 10 mg	Buspirone Cmax ↑ 13.4-fold, AUC ↑ 19.2-fold	Use with caution
Midazolam (i.v.) 7.5 mg	Midazolam concentration ↑ Although itraconazole has not been studied directly, it may increase oromucosal midazolam concentration	Use with caution
Risperidone 2–8 mg/day	Risperidone and active metabolite concentration ↑	Use with caution
Zopiclone 7.5 mg	Zopiclone Cmax ↑ 30%, AUC ↑ 70%	Use with caution
Cariprazine, galantamine, haloperidol, reboxetine, venlafaxine	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Respiratory system agents
Lumacaftor/ivacaftor orally 200/250 mg twice daily	Ivacaftor Cmax ↑ 3.6-fold, AUC ↑ 4.3-fold Lumacaftor Cmax ↔, AUC ↔	Not recommended
Ivacaftor	Although itraconazole has not been studied directly, it may increase ivacaftor concentration	Use with caution
Sex hormones and modulators of the genital system; other gynaecological agents
Cabergoline, dienogest, ulipristal	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Urinary system agents
Avanafil, dapoxetine, darifenacin	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Contraindicated
Fesoterodine	Although itraconazole has not been studied directly, it may increase concentrations of active metabolites, 5-hydroxymethyltolterodine	Contraindicated in moderate or severe renal or hepatic impairment. Avoid concomitant use in mild renal or hepatic impairment. In patients with normal renal and hepatic function: use with caution, maximum fesoterodine dose 4 mg
Solifenacin	Although itraconazole has not been studied directly, it may increase solifenacin concentration	Contraindicated in severe renal impairment. Contraindicated in moderate or severe hepatic impairment. Use with caution in all other patients, maximum solifenacin dose 5 mg.
Vardenafil	Although itraconazole has not been studied directly, it may increase vardenafil concentration	Contraindicated in patients aged 75 years and older; not recommended for other patients.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Although itraconazole has not been studied directly, it may increase concentrations of these drugs	Use with caution
Oxybutynin 5 mg	Oxybutynin Cmax ↑ 2-fold, AUC ↑ 2-fold N-desethyloxybutynin Cmax ↔, AUC ↔ Although itraconazole has not been studied directly, it may increase transdermal oxybutynin concentration	Use with caution
Other medicinal products and substances
Colchicine	Although itraconazole has not been studied directly, it may increase colchicine concentration	Contraindicated in patients with renal or hepatic impairment. Not recommended for other patients.
Eliglustat	Although itraconazole has not been studied directly, it may increase eliglustat concentration	Contraindicated for poor metabolizers (PM) of CYP2D6. Contraindicated for intermediate (IM) or extensive metabolizers (EM) taking a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IM and EM. For EM CYP2D6 with mild hepatic impairment, consider eliglustat dose of 84 mg/day.
Cinacalcet	Although itraconazole has not been studied directly, it may increase cinacalcet concentration	Use with caution

Special precautions for use.

Cross-sensitivity

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

Effect on the heart

Transient, asymptomatic decreases in left ventricular ejection fraction have been reported in studies with intravenous itraconazole in healthy volunteers, which reversed before the next infusion. The clinical significance of these findings for oral formulations is not established.

It is known that itraconazole has a negative inotropic effect. Cases of congestive heart failure associated with itraconazole use have been reported. According to spontaneous reports, the incidence of congestive heart failure was higher with a total daily dose of 400 mg compared to lower daily doses. Thus, the risk of heart failure may increase depending on the total daily dose of itraconazole.

The drug should not be used in patients with current or past history of congestive heart failure, except when the expected benefit significantly outweighs the potential risk. In individual benefit-risk assessment, factors such as severity of diagnosis, dosing regimen and duration of treatment (total daily dose), and individual risk factors for developing congestive heart failure should be considered. These risk factors include presence of cardiac disorders such as ischemic heart disease or valvular disease; severe lung diseases, including chronic obstructive pulmonary disease; renal failure or other conditions associated with edema. Such patients should be informed about signs and symptoms of congestive heart failure, and treatment should be administered cautiously with monitoring for signs and symptoms of heart failure. If such signs or symptoms occur during treatment, the drug should be discontinued.

Calcium channel blockers may have a negative inotropic effect, which may be potentiated by the same effect of itraconazole. Also, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when using itraconazole concomitantly with calcium channel blockers due to 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 cases of acute liver failure with fatal outcome, has been reported very rarely with itraconazole. Most of these cases occurred in patients with pre-existing liver disease who were treated for systemic indications, had other serious illnesses and/or were taking other hepatotoxic drugs. In some patients, no obvious risk factors for liver disease were identified. Some of these cases occurred within the first month of treatment, including the first week. Therefore, monitoring of liver function is advisable in patients taking itraconazole. Patients should be warned to seek immediate medical attention if signs or symptoms of hepatitis occur, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. If these symptoms occur, treatment should be stopped immediately and liver function tests should be performed.

Limited data are available on the oral use of itraconazole in patients with hepatic impairment. This medicinal product should be used with caution in such patients. Close monitoring of patients with impaired liver function who are receiving itraconazole is recommended. When making decisions about treatment with other drugs metabolized by CYP3A4, the prolonged elimination half-life of itraconazole observed in clinical studies in patients with cirrhosis who received single doses of itraconazole capsules should be taken into account.

Itraconazole is not recommended in patients with elevated liver enzymes, active liver disease, or manifestations of hepatotoxicity due to other drugs, unless in severe or life-threatening situations where the expected benefit outweighs the risk. Monitoring of liver function is recommended in patients with impaired liver function or those with a history of hepatotoxicity caused by other medicinal products (see section "Pharmacokinetics").

Reduced gastric acidity

Absorption of itraconazole is reduced in conditions of low gastric acidity. In patients with reduced gastric acidity due to disease (e.g., achlorhydria) or concomitant use of other drugs (e.g., drugs reducing gastric acidity), it is recommended to administer the drug with acidic beverages (e.g., non-diet cola). Antifungal activity should be monitored and the dose of itraconazole increased if necessary (see section "Interaction with other medicinal products and other forms of interaction").

Children

The safety and efficacy of the drug in children (under 18 years of age) have not been established (see sections "Adverse reactions" and "Pharmacokinetics").

Elderly patients

Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole should not be used in elderly patients unless the benefit outweighs the potential risk. In general, dose selection for elderly patients should be based on hepatic, renal, or cardiac function, as well as the presence of comorbidities or concomitant medications.

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 failure. Caution should be exercised when administering the drug to this patient group, 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 sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Hearing usually recovers after discontinuation of itraconazole therapy, but in some patients hearing loss is irreversible.

Immunocompromised patients

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

Patients with life-threatening systemic fungal infections

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

Patients with AIDS

The physician should assess the need for maintenance therapy in 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.

Neuropathy

If neuropathy occurs related to itraconazole use, treatment should be discontinued.

Cystic fibrosis

Variable therapeutic levels of itraconazole have been observed in patients with cystic fibrosis after administration of oral itraconazole solution 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 older, but in none of the patients under 16 years of age. If a patient does not respond to itraconazole, consideration should be given to switching to alternative therapy.

Carbohydrate metabolism disorders

The product contains sucrose. If a patient has intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product. This medicinal product should not be used in patients with rare hereditary conditions of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Cross-resistance

If systemic candidiasis is suspected to be caused by Candida species resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, susceptibility testing should be performed before initiating treatment with itraconazole.

Potential for interaction

Concomitant use of itraconazole and certain medicinal products may lead to changes in the efficacy of itraconazole and/or the concomitantly administered drug, to the occurrence of adverse reactions that may be life-threatening, and/or to sudden fatal outcomes. Medicinal products that are contraindicated or should be used 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

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

In animal studies, itraconazole showed reproductive toxicity.

Data on the use of itraconazole during pregnancy are limited. Cases of developmental abnormalities such as skeletal malformations, genitourinary tract, cardiovascular system and eye abnormalities, chromosomal abnormalities, and multiple congenital malformations have been reported. A causal relationship with itraconazole has not been established.

Epidemiological data on the effect of itraconazole in women during the first trimester of pregnancy (mainly in patients who used it for short-term treatment of vulvovaginal candidiasis) did not show an increased risk of congenital malformations compared to women who did not use teratogenic drugs.

Women of childbearing potential

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

Breastfeeding period

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 case of doubt, the woman should discontinue breastfeeding.

Fertility

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

Ability to affect 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 adverse consequences while driving or operating machinery.

Administration and dosage.

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

Table 3

Treatment regimens for adults for each indication:

Indications	Dose	Duration	Notes
Vulvovaginal candidiasis	200 mg twice daily	1 day
Tinea versicolor	200 mg once daily	7 days
Crural dermatomycosis, trunk dermatophytosis	100 mg once daily	15 days
Crural dermatomycosis, trunk dermatophytosis	200 mg once daily	7 days
Tinea pedis, tinea manuum	100 mg once daily	30 days
Oropharyngeal candidiasis	100 mg once daily	15 days	Dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS due to impaired drug absorption in these patients.
Onychomycosis (nail plate involvement of toes, 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 nail plate infection treatment. This is due to the fact that itraconazole is eliminated from skin, nail, and mucosal tissues more slowly 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	Dosage1	Notes
Aspergillosis	200 mg once daily	Dose increase to 200 mg twice daily in case of invasive or disseminated disease
Candidiasis	100–200 mg once daily	Dose increase to 200 mg twice daily in case of invasive or disseminated disease
Cryptococcosis (without signs of meningitis)	200 mg once daily
Cryptococcal meningitis	200 mg twice daily	Maintenance therapy (see section "Special precautions").
Histoplasmosis	from 200 mg once daily to 200 mg twice daily
Maintenance treatment in AIDS patients	200 mg once daily	See note on impaired absorption below.
Prophylaxis in patients with neutropenia	200 mg once daily	See note on impaired absorption below.
1 Treatment duration should be adjusted according to clinical response. Impaired absorption in AIDS patients and in patients with neutropenia may lead to low itraconazole blood concentrations and reduced efficacy. In such cases, monitoring of itraconazole blood levels is recommended, and dose may be increased up to 200 mg twice daily if necessary.

Elderly patients.

The use of the drug is not recommended in elderly patients (see section "Special precautions").

Patients with renal impairment.

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

Patients with hepatic impairment.

Clinical data on the use of oral formulations of itraconazole in patients with impaired liver function 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 drug in children is not recommended.

Overdose.

In general, adverse reactions reported in cases of overdose had a similar profile to adverse reactions occurring during itraconazole administration (see section "Adverse reactions"). In case of overdose, supportive measures should be taken. Itraconazole cannot be removed by hemodialysis. There is no specific antidote. For current recommendations on overdose management, contact a poison control center.

Adverse Reactions

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

The adverse reactions listed below are grouped by organ systems. Within each group, reactions are listed by frequency. Frequency is defined as follows: 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, tremor.

Eye disorders:

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

Ear and labyrinth disorders:

Rare – temporary or permanent hearing loss*, tinnitus.

Cardiac disorders:

Rare – congestive heart failure*.

Respiratory, thoracic and mediastinal disorders:

Rare – dyspnea.

Gastrointestinal disorders:

Common – abdominal pain, nausea.

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

Rare – pancreatitis.

Hepatobiliary disorders:

Uncommon – liver function abnormalities.

Rare – severe hepatotoxicity (including several cases of severe acute liver failure with fatal outcome)*, hyperbilirubinemia.

Skin and subcutaneous tissue disorders:

Uncommon – urticaria, rash, pruritus.

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

Renal and urinary disorders:

Rare – polyuria.

Reproductive system and breast disorders:

Uncommon – menstrual disorders.

Rare – erectile dysfunction.

General disorders and administration site conditions:

Uncommon – edema.

Investigations:

Rare – increased blood creatine phosphokinase levels.

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

List of selected adverse reactions.

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

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

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

Psychiatric disorders: confusion.

Nervous system disorders: peripheral neuropathy*, dizziness, somnolence, 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 (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels, increased lactate dehydrogenase levels, increased blood urea levels, increased gamma-glutamyl transferase (GGT) levels, increased liver enzyme levels, abnormalities in urine analysis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through 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, out of reach of children, at a temperature not exceeding 25 °C.

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

Prescription status. Prescription only.

Manufacturer.

Artura Pharmaceuticals Pvt. Ltd.

Manufacturer's address and location of operations.

1505 Portia Road, Sri City SEZ, Setyawedu Mandal, Chittoor District – 517 588, Andhra Pradesh State, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTION

for medical use of the medicinal product

ITRUNGAR

(ITRUNGAR)

Composition:

Active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

Excipients:

Pellets contain: hydroxypropylmethylcellulose, corn starch, sucrose;

Capsule shell contains:

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

Cap: FD&C Green No. 3, titanium dioxide (E 171), methylparaben (E 218), propylparaben (E 219), sodium lauryl sulfate, purified water, gelatin.

Dosage form. Capsules.

Main physicochemical characteristics: hard gelatin capsules with a yellow body and green cap or vice versa (size 0); the capsule contents are pellets ranging from white to grey in color.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole and tetrazole 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; inhibition of its synthesis underlies the antifungal effect.

Breakpoint values for itraconazole have been established only for Candida spp. For superficial fungal infections (CLSI M27-A2, breakpoints have not been defined by EUCAST methodology). CLSI breakpoint values: 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 generally ≤1 µg/mL. These include dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis, and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.), Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis; Pseudallescheria boydii; Penicillium marneffei; and other yeast and fungal species.

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

The main types of fungi not inhibited by itraconazole are 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. Known mechanisms include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of efflux transporters, resulting in increased export of itraconazole from fungal cells (thus removing itraconazole from its target site). Cross-resistance among azole antifungal agents has been observed within Candida species; however, resistance to one azole does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics

General Pharmacokinetic Characteristics

Peak plasma concentration after oral administration of itraconazole is reached within 2 to 5 hours. Due to non-linear pharmacokinetics, itraconazole accumulates in plasma following multiple 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 elimination 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. The maximum plasma concentration of unchanged drug after oral capsule administration is reached within 2–5 hours. 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 decreased 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 if Itrungar capsules are taken with acidic beverages (e.g., non-diet cola). When a single 200 mg dose of Itrungar was administered on an empty stomach with non-diet cola after ranitidine (an H2-receptor antagonist), absorption of itraconazole was comparable to that observed after administration of Itrungar capsules alone.

Distribution

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

Biotransformation

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

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

Renal Impairment

Data on the use of oral itraconazole in patients with renal dysfunction are limited. A pharmacokinetic study using a single 200 mg dose of itraconazole (4 capsules of 50 mg) was conducted in 3 groups of patients with renal impairment (uremia: n=7, hemodialysis: n=7, continuous ambulatory peritoneal dialysis: n=5). In patients with uremia and a mean creatinine clearance of 13 mL/min × 1.73 m², AUC-based concentrations were slightly lower compared to healthy volunteers. The study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0–8h). Plasma concentration profiles showed substantial inter-subject variability in all 3 groups.

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

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

Pediatric Population

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

Clinical characteristics.

Indications.

Vulvovaginal candidiasis;
Pityriasis versicolor;
Dermatomycoses caused by itraconazole-sensitive 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 infections.

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

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 and CYP3A4 substrates is contraindicated (see sections «Interaction with other medicinal products and other types of interactions» and «Special warnings and precautions for use»). These include:

Analgesics; anesthetics
Ergot alkaloids (e.g., dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Antibacterials for systemic use; antimycobacterials; antifungals for systemic use
Isavuconazole
Antihelminthics; antiprotozoals
Halofantrine
Antihistamines for systemic use
Astemizole	Mizolastine	Terfenadine
Antineoplastics
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukemia during the initiation and dose-titration phases of venetoclax)
Antiplatelets
Dabigatran	Ticagrelor
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiologic therapy; diuretics)
Aliskiren	Eplerenone	Quinidine
Bepridil	Finerenone	Ranolazine
Disopyramide	Ivabradine	Sildenafil (pulmonary hypertension)
Dofetilide	Lercanidipine
Dronedarone	Nisoldipine
Gastrointestinal agents, including antidiarrheals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; agents used in functional gastrointestinal disorders
Cisapride	Domperidone	Naloxegol
Lipid-regulating drugs
Lovastatin	Lomitapide	Simvastatin
Psychoanaleptics; psycholeptics (e.g., antipsychotics, anxiolytics, and hypnotics)
Lurasidone	Pimozide	Sertindole
Midazolam (oral)	Quetiapine	Triazolam
Drugs affecting the urinary system
Avanafil	Darifenacin	Solifenacin (in patients with severe renal impairment 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 poor metabolizers (PM), intermediate metabolizers (IM), or rapid metabolizers (RM) of CYP2D6 and who are taking a strong or moderate CYP2D6 inhibitor)

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 or other serious infections (see section "Special precautions and warnings").

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

Women of childbearing potential should use reliable contraceptive methods throughout the entire course of itraconazole treatment and until the end of the menstrual cycle after completion of treatment.

Interaction with other medicinal products and other forms of interaction.

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

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

Examples of drugs that may affect itraconazole plasma concentrations, categorized by drug class, are listed in Table 1 below.

Examples of drugs whose plasma concentrations may be affected by itraconazole are listed in Table 2 below. Potential changes in safety or efficacy of interacting drugs are not taken into account. For additional information, refer to the respective product information for the medicinal product.

Combinations of itraconazole with drugs described in Tables 1 and 2 are classified as contraindicated, not recommended, or to be used with caution, depending on the degree of concentration increase and the safety profile of the interacting drug (see also sections "Contraindications" and "Special precautions and warnings"). The interaction potential of the listed drugs was assessed based on pharmacokinetic study data of itraconazole or other strong CYP3A4 inhibitors (e.g., ketoconazole) in humans and/or in vitro data:

"Contraindicated": These drugs must not be used concomitantly with itraconazole or within two weeks after discontinuation of itraconazole treatment.
"Not recommended": Concomitant use of these drugs during and 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, clinical monitoring for signs or symptoms of increased or prolonged pharmacological effect of the co-administered drug is recommended, and its dose should be reduced or treatment discontinued if necessary. Plasma concentration monitoring of the co-administered drug is recommended if needed.
"Use with caution": Careful monitoring is recommended when used concomitantly with itraconazole. Close observation of patients for signs or symptoms of increased or prolonged pharmacological effect of the co-administered drug is recommended, and dose reduction may be necessary. Plasma concentration monitoring of the co-administered drug is recommended if needed.

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

After discontinuation of treatment, itraconazole plasma concentrations decline to the limit of quantification within 7–14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in patients concomitantly receiving CYP3A4 inhibitors, the decline in plasma concentration may be more gradual. This is particularly relevant for drugs whose metabolism is affected by itraconazole (see section "Pharmacokinetics").

Table 1

Drugs that may affect itraconazole plasma concentrations

Medicinal products (oral single dose unless otherwise stated) within class	Expected/potential effect on itraconazole levels: ↑ increase ↔ no change ↓ decrease	Clinical comment (see additional information above, as well as sections “Contraindications” and “Special precautions for use”)
Antibacterials for systemic use; antimycobacterials
Isoniazid	Although isoniazid has not been studied directly, it is likely to reduce itraconazole concentration	Not recommended
Rifampicin orally 600 mg once daily	Itaconazole AUC ↓	Not recommended
Rifabutin orally 300 mg once daily	Itaconazole Cmax ↓ 71%, AUC ↓ 74%	Not recommended
Ciprofloxacin orally 500 mg twice daily	Itaconazole Cmax ↑ 53%, AUC ↑ 82%	Use with caution
Erythromycin 1 g	Itaconazole Cmax ↑ 44%, AUC ↑ 36%	Use with caution
Clarithromycin orally 500 mg twice daily	Itaconazole Cmax ↑ 90%, AUC ↑ 92%	Use with caution
Antiepileptics
Carbamazepine, phenobarbital	Although these drugs have not been studied directly, they are likely to reduce itraconazole concentration	Not recommended
Phenytoin orally 300 mg once daily	Itaconazole Cmax ↓ 83%, AUC ↓ 93% Hydroxyitraconazole Cmax ↓ 84%, AUC ↓ 95%	Not recommended
Antineoplastic agents
Idelalisib	Although idelalisib has not been studied directly, it is likely to increase itraconazole concentration	Use with caution
Antivirals for systemic use
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Although these drugs have not been studied directly, they are expected to increase itraconazole concentration	Contraindicated
Efavirenz 600 mg	Itaconazole Cmax ↓ 37%, AUC ↓ 39% Hydroxyitraconazole Cmax ↓ 35%, AUC ↓ 37%	Not recommended
Nevirapine orally 200 mg once daily	Itaconazole Cmax ↓ 38%, AUC ↓ 62%	Not recommended
Cobicistat, darunavir (boosted), elvitegravir (ritonavir-boosted), fosamprenavir (ritonavir-boosted), ritonavir, saquinavir (ritonavir-boosted)	Although these drugs have not been studied directly, they are expected to increase itraconazole concentration	Use with caution
Indinavir orally 800 mg three times daily	Itaconazole concentration ↑	Use with caution
Calcium channel blockers
Diltiazem	Although diltiazem has not been studied directly, it may increase itraconazole concentration	Use with caution
Drugs for treatment of disorders related to 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, rabeprozole)	Itaconazole Cmax ↓, AUC ↓	Use with caution
Drugs affecting the respiratory system
Lumacaftor/ivacaftor orally 200/250 mg twice daily	Itaconazole concentration ↓	Not recommended
Other medicinal products and substances
St. John’s wort (Hypericum perforatum)	Although St. John’s wort has not been studied directly, it is likely to reduce itraconazole concentration	Not recommended

Table 2

Examples of drugs whose plasma concentrations may be affected by itraconazole

Medicinal products (oral single dose unless otherwise stated) within class	Expected/potential effect on itraconazole levels: ↑ increase ↔ no change ↓ decrease	Clinical comment (see additional information above and sections "Contraindications" and "Special precautions for use")
Analgesics; anaesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Eletriptan, fentanyl	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Not recommended
Alfentanil, buprenorphine (intravenous [i.v.] and sublingual), cannabinoids, methadone, sufentanil	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Oxycodone oral 10 mg	Oxycodone oral Cmax ↑ 45%, AUC ↑ 2.4-fold	Use with caution
Oxycodone i.v. 0.1 mg/kg	Oxycodone i.v. AUC ↑ 51%	Use with caution
Systemic antibacterial agents; antimycobacterial agents; systemic antifungal agents
Isavuconazole	Although itraconazole has not been directly studied, it may increase isavuconazole concentration	Contraindicated
Bedaquiline	Although itraconazole has not been directly studied, it may increase bedaquiline concentration	Not recommended
Rifabutin oral 300 mg once daily	Rifabutin concentration ↑ (extent unknown)	Not recommended
Clarithromycin oral 500 mg twice daily	Clarithromycin concentration ↑	Use with caution
Delamanid	Although itraconazole has not been directly studied, it may increase delamanid concentration	Use with caution
Antiepileptic drugs
Carbamazepine	Although itraconazole has not been directly studied, it may increase carbamazepine concentration	Not recommended
Anti-inflammatory and antirheumatic drugs
Meloxicam 15 mg	Meloxicam Cmax ↓ 64%, AUC ↓ 37%	Use with caution
Anthelmintics; antiprotozoal agents
Halofantrine	Although itraconazole has not been directly studied, it may increase halofantrine concentration	Contraindicated
Artemether-lumefantrine, praziquantel	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Quinine 300 mg	Quinine Cmax ↔, AUC ↑ 96%	Use with caution
Systemic antihistamines
Astemizole, mizolastine, terfenadine	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Ebastine 20 mg	Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2-fold Carbastine Cmax ↔, AUC ↑ 3.1-fold	Not recommended
Bilastine, rupatadine	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Antineoplastic agents
Irinotecan	Although itraconazole has not been directly studied, it may increase concentrations of irinotecan and its active metabolite	Contraindicated
Venetoclax	Although itraconazole has not been directly studied, it may increase venetoclax concentration	Contraindicated in patients with chronic lymphocytic leukaemia during initiation and dose-titration phases of venetoclax. Otherwise not recommended unless benefits outweigh risks. Refer to venetoclax product 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)	Although itraconazole has not been directly studied, it is likely to increase concentrations of these drugs, except for cabazitaxel and regorafenib. No statistically significant changes in cabazitaxel exposure, but high variability observed. AUC of regorafenib is expected to decrease (based on active moiety)	Not recommended
Cobimetinib 10 mg	Cobimetinib Cmax ↑ 3.2-fold, AUC ↑ 6.7-fold	Not recommended
Entrectinib	Entrectinib Cmax ↑ 73%, AUC ↑ 6.0-fold	Not recommended
Olapatari	Olapatari Cmax ↑ 40%, AUC ↑ 2.7-fold	Not recommended
Talazoparib	Talazoparib Cmax ↑ 40%, AUC ↑ 56%	Not recommended
Alitretinoin (oral), bortezomib, brentuximab vedotin, erlotinib, idelalisib, imatinib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, tretinoin (oral)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Busulfan 1 mg/kg every 6 hours	Busulfan Cmax ↑, AUC ↑	Use with caution
Gefitinib 250 mg	Gefitinib 250 mg Cmax ↑, AUC ↑ 78%	Use with caution
Pemigatinib	Pemigatinib Cmax ↑ 17%, AUC ↑ 91%	Use with caution
Antithrombotic agents
Dabigatran, ticagrelor	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Not recommended
Cilostazol, coumarins (e.g. warfarin)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Systemic antiviral agents
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase paritaprevir concentration	Contraindicated
Elbasvir/grazoprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Not recommended
Cobicistat, elvitegravir (ritonavir-boosted), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Indinavir oral 800 mg three times daily	Indinavir Cmax ↔, AUC ↑	Use with caution
Cardiovascular system (agents acting on the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiac therapy; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, finerenone, ivabradine, lercanidipine, nisoldipine, ranolazine, sildenafil (pulmonary hypertension)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Aliskiren 150 mg	Aliskiren Cmax ↑ 5.8-fold, AUC ↑ 6.5-fold	Contraindicated
Quinidine 100 mg	Quinidine Cmax ↑ 59%, AUC ↑ 2.4-fold	Contraindicated
Felodipine 5 mg	Felodipine Cmax ↑ 7.8-fold, AUC ↑ 6.3-fold	Not recommended
Riociguat, tadalafil (pulmonary hypertension)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (e.g. amlodipine, isradipine, nifedipine, nimodipine), verapamil	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Digoxin 0.5 mg	Digoxin Cmax ↑ 34%, AUC ↑ 68%	Use with caution
Nadolol 30 mg	Nadolol Cmax ↑ 4.7-fold, AUC ↑ 2.2-fold	Use with caution
Systemic corticosteroids; drugs for obstructive respiratory diseases
Ciclesonide, salmeterol	Although itraconazole has not been directly studied, it may increase salmeterol and active metabolite of ciclesonide concentrations	Not recommended
Budesonide inhaled 1 mg single dose	Budesonide inhaled Cmax ↑ 65%, AUC ↑ 4.2-fold Budesonide (other forms) concentration ↑	Use with caution
Dexamethasone i.v. 5 mg Dexamethasone oral 4.5 mg	Dexamethasone i.v.: Cmax ↔, AUC ↑ 3.3-fold Dexamethasone oral: Cmax ↑ 69%, AUC ↑ 3.7-fold	Use with caution
Fluticasone inhaled 1 mg twice daily	Fluticasone concentration ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone oral Cmax ↑ 92%, AUC ↑ 3.9-fold Methylprednisolone i.v. AUC ↑ 2.6-fold	Use with caution
Fluticasone nasal	Although itraconazole has not been directly studied, it is likely to increase intranasally administered fluticasone concentration	Use with caution
Drugs used in diabetes
Repaglinide 0.25 mg	Repaglinide Cmax ↑ 47%, AUC ↑ 41%	Use with caution
Saxagliptin	Although itraconazole has not been directly studied, it may increase saxagliptin concentration	Use with caution
Gastrointestinal drugs including antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents; antiemetics and antinauseants; laxatives; drugs used in functional gastrointestinal disorders
Cisapride, naloxegol	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Domperidone 20 mg	Domperidone Cmax ↑ 2.7-fold, AUC ↑ 3.2-fold	Contraindicated
Aprepitant, loperamide, netupitant	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Although itraconazole has not been directly studied, it may increase sirolimus concentrations	Not recommended
Cyclosporine, tacrolimus	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Tacrolimus i.v. 0.03 mg/kg once daily	Tacrolimus i.v. concentration ↑	Use with caution
Lipid-regulating drugs
Lomitapide	Although itraconazole has not been directly studied, it may increase lomitapide concentrations	Contraindicated
Lovastatin 40 mg	Lovastatin Cmax ↑ 14.5 – >20-fold, AUC ↑ >14.8 – >20-fold Lovastatin acid Cmax ↑ 11.5–13-fold, AUC ↑ 15.4–20-fold	Contraindicated
Simvastatin 40 mg	Simvastatin acid Cmax ↑ 17-fold, AUC ↑ 19-fold	Contraindicated
Atorvastatin	Atorvastatin acid Cmax ↑ up to 2.5-fold, AUC ↑ from 40% to 3-fold	Not recommended
Psychostimulants; psycholeptics (e.g. antipsychotics, anxiolytics, hypnotics)
Lurasidone, pimozide, quetiapine, sertindole	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Midazolam (oral) 7.5 mg	Midazolam (oral) Cmax ↑ 2.5–3.4-fold, AUC ↑ 6.6–10.8-fold	Contraindicated
Triazolam 0.25 mg	Triazolam Cmax ↑, AUC ↑	Contraindicated
Alprazolam 0.8 mg	Alprazolam Cmax ↔, AUC ↑ 2.8-fold	Use with caution
Aripiprazole 3 mg	Aripiprazole Cmax ↑ 19%, AUC ↑ 48%	Use with caution
Brothizolam 0.5 mg	Brothizolam Cmax ↔, AUC ↑ 2.6-fold	Use with caution
Buspirone 10 mg	Buspirone Cmax ↑ 13.4-fold, AUC ↑ 19.2-fold	Use with caution
Midazolam (i.v.) 7.5 mg	Midazolam concentration ↑ Although itraconazole has not been directly studied, it may increase concentration of oromucosal midazolam	Use with caution
Risperidone 2–8 mg/day	Risperidone and active metabolite concentrations ↑	Use with caution
Zopiclone 7.5 mg	Zopiclone Cmax ↑ 30%, AUC ↑ 70%	Use with caution
Cariprazine, galantamine, haloperidol, reboxetine, venlafaxine	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Drugs affecting the respiratory system
Lumacaftor/ivacaftor oral 200/250 mg twice daily	Ivacaftor Cmax ↑ 3.6-fold, AUC ↑ 4.3-fold Lumacaftor Cmax ↔, AUC ↔	Not recommended
Ivacaftor	Although itraconazole has not been directly studied, it may increase ivacaftor concentration	Use with caution
Sex hormones and modulators of the reproductive system; other gynaecological drugs
Cabergoline, dienogest, ulipristal	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Drugs affecting the urinary system
Avanafil, dapoxetine, darifenacin	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Contraindicated
Fesoterodine	Although itraconazole has not been directly studied, it may increase concentrations of active metabolites, 5-hydroxymethyltolterodine	Contraindicated in moderate or severe renal or hepatic impairment. Avoid concomitant use in mild renal or hepatic impairment. In patients with normal renal and hepatic function: use with caution, maximum fesoterodine dose 4 mg
Solifenacin	Although itraconazole has not been directly studied, it may increase solifenacin concentration	Contraindicated in severe renal impairment. Contraindicated in moderate or severe hepatic impairment. Use with caution in all other patients, maximum solifenacin dose 5 mg.
Vardenafil	Although itraconazole has not been directly studied, it may increase vardenafil concentration	Contraindicated in patients aged 75 years and older; not recommended for other patients.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Although itraconazole has not been directly studied, it may increase concentrations of these drugs	Use with caution
Oxybutynin 5 mg	Oxybutynin Cmax ↑ 2-fold, AUC ↑ 2-fold N-desethyloxybutynin Cmax ↔, AUC ↔ Although itraconazole has not been directly studied, it may increase oxybutynin concentration after transdermal administration	Use with caution
Other medicinal products and substances
Colchicine	Although itraconazole has not been directly studied, it may increase colchicine concentration	Contraindicated in patients with renal or hepatic impairment. Not recommended for other patients.
Eliglustat	Although itraconazole has not been directly studied, it may increase eliglustat concentration	Contraindicated for poor metabolizers (PM) of CYP2D6. Contraindicated for intermediate (IM) or extensive metabolizers (EM) taking strong or moderate CYP2D6 inhibitors. Use with caution in CYP2D6 IM and EM. For EM of CYP2D6 with mild hepatic impairment, consider eliglustat dose of 84 mg/day.
Cinacalcet	Although itraconazole has not been directly studied, it may increase cinacalcet concentration	Use with caution

Special precautions for use.

Cross-sensitivity

There are no data regarding cross-sensitivity between itraconazole and other azole antifungal agents. It is recommended to administer itraconazole with caution in patients who are hypersensitive to other azoles.

Cardiac effects

Transient, asymptomatic decreases in left ventricular ejection fraction have been reported in healthy volunteers receiving intravenous itraconazole in clinical studies; these changes reversed before the next infusion. The clinical relevance of these findings for oral formulations is unknown.

It is known that itraconazole has a negative inotropic effect. Cases of congestive heart failure associated with itraconazole use have been reported. According to 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 with the total daily dose of itraconazole.

The drug should not be used in patients with current or past history of congestive heart failure, except when the expected benefit clearly outweighs the potential risk. In individual benefit-risk assessment, factors such as severity of diagnosis, dosing regimen and duration of treatment (total daily dose), and individual risk factors for developing congestive heart failure should be considered. These risk factors include pre-existing cardiac conditions such as ischemic heart disease or valvular disorders; severe pulmonary diseases, including chronic obstructive pulmonary disease; renal insufficiency; or other conditions associated with edema. Such patients should be informed about the signs and symptoms of congestive heart failure, and treatment should be administered cautiously with close monitoring for signs and symptoms of heart failure. If such signs or symptoms occur during treatment, the drug should be discontinued immediately.

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

Hepatic effects

Severe hepatotoxicity, including cases of acute liver failure with fatal outcomes, has been reported very rarely with itraconazole use. Most of these cases occurred in patients with pre-existing liver disease receiving systemic treatment, those with other serious underlying conditions, and/or those taking other hepatotoxic drugs. In some patients, no obvious risk factors for liver disease were identified. Some of these cases occurred within the first month of treatment, including the first week. Therefore, monitoring of liver function is advisable in patients receiving itraconazole. Patients should be warned to seek immediate medical attention if they experience signs or symptoms of hepatitis, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed.

Limited data are available on the oral use of itraconazole in patients with hepatic impairment. This medicinal product should be used with caution in such patients. Close monitoring of patients with impaired liver function who are receiving 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.

Itraconazole is not recommended in patients with elevated liver enzymes, active liver disease, or a history of hepatotoxicity due to other medications, unless in severe or life-threatening situations where the expected benefit outweighs the risk. Monitoring of liver function is recommended in patients with hepatic dysfunction or a history of hepatotoxicity induced by other medicinal products (see section "Pharmacokinetics").

Reduced gastric acidity

Reduced gastric acidity impairs the absorption of itraconazole. Patients with reduced gastric acidity due to disease (e.g., achlorhydria) or concomitant use of other medications (e.g., acid-reducing agents) are recommended to take the medicinal product with acidic beverages (e.g., non-diet cola). Antifungal activity should be monitored, and the dose of itraconazole should be increased if necessary (see section "Interaction with other medicinal products and other forms of interaction").

Children

The safety and efficacy of the medicinal product in children (under 18 years of age) have not been established (see sections "Adverse reactions" and "Pharmacokinetics").

Elderly patients

Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole should not be used in elderly patients unless the benefit outweighs the potential risk. In general, dose selection for elderly patients should take into account hepatic, renal, or cardiac function, as well as comorbid conditions and concomitant medications.

Renal impairment

Data on the oral use of itraconazole in patients with renal impairment are limited. The oral bioavailability of itraconazole may be reduced in patients with renal insufficiency. Caution should be exercised when administering the drug to this patient group, and dose adjustment should be considered.

Hearing loss

Cases of temporary or permanent hearing loss have been reported in patients receiving itraconazole. In some cases, hearing loss occurred during concomitant use with quinidine, which is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Hearing usually recovers after discontinuation of itraconazole therapy, but in some patients, hearing loss may be irreversible.

Immunocompromised patients

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

Patients with life-threatening systemic fungal infections

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

Patients with AIDS

Neuropathy

If neuropathy occurs related to itraconazole use, treatment should be discontinued.

Cystic fibrosis

Variable therapeutic levels of itraconazole have been observed in patients with cystic fibrosis after administration of oral itraconazole solution at a dose of 2.5 mg/kg twice daily. A steady-state concentration > 250 ng/mL was achieved in approximately 50% of patients aged 16 years and older, but in none of the patients under 16 years of age. If a patient does not respond to itraconazole, consideration should be given to switching to alternative therapy.

Carbohydrate metabolism disorders

The product contains sucrose. Patients with diagnosed intolerance to certain sugars should consult their physician before taking this medicinal product. This medicinal product should not be administered to patients with rare hereditary conditions of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Cross-resistance

In systemic candidiasis, if there is suspicion that the Candida species causing the infection are resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, susceptibility testing should be performed before initiating itraconazole therapy.

Potential for interaction

Concomitant use of itraconazole with certain medicinal products may lead to altered efficacy of itraconazole and/or the co-administered drug, serious or life-threatening adverse reactions, and/or sudden death. Medicinal products that are contraindicated or require cautious co-administration with itraconazole are listed in the section "Interaction with other medicinal products and other forms of interaction".

Use during pregnancy or breastfeeding.

Pregnancy

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

In animal studies, itraconazole has shown reproductive toxicity.

Data on the use of itraconazole during pregnancy are limited. Cases of developmental abnormalities, including skeletal, urogenital, cardiovascular, and ocular malformations, chromosomal abnormalities, and multiple congenital defects, have been reported. A causal relationship with itraconazole has not been established.

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

Women of childbearing potential

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

Lactation

Very small amounts of itraconazole pass into breast milk. Therefore, during lactation, the potential risk to the infant should be weighed against the expected benefit of itraconazole treatment for the mother. In case of doubt, the woman should discontinue breastfeeding.

Fertility

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

Ability to drive and use machines.

Studies on the effect on the ability to drive and use machines have not been conducted. The possibility of adverse reactions such as dizziness, visual disturbances, and hearing loss (see section "Adverse reactions") should be considered, as these may impair the ability to drive or operate machinery.

Dosage and Administration.

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

Table 3

Treatment regimens for adults for each indication:

Indications	Dose	Duration	Notes
Vulvovaginal candidiasis	200 mg twice daily	1 day
Tinea versicolor	200 mg once daily	7 days
Crural dermatomycosis, tinea of the trunk	100 mg once daily	15 days
Crural dermatomycosis, tinea of the trunk	200 mg once daily	7 days
Tinea pedis, tinea manuum	100 mg once daily	30 days
Oropharyngeal candidiasis	100 mg once daily	15 days	Dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS due to impaired drug absorption in these patients.
Onychomycosis (nail plate involvement of toes, 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 elimination of itraconazole from skin, nail, and mucosal tissues is slower 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	Dosage1	Notes
Aspergillosis	200 mg once daily	Dose increase to 200 mg twice daily in case of invasive or disseminated disease
Candidiasis	100–200 mg once daily	Dose increase to 200 mg twice daily in case of invasive or disseminated disease
Cryptococcosis (without signs of meningitis)	200 mg once daily
Cryptococcal meningitis	200 mg twice daily	Maintenance therapy (see section "Special precautions").
Histoplasmosis	from 200 mg once daily to 200 mg twice daily
Maintenance treatment in AIDS patients	200 mg once daily	See note on impaired absorption below.
Prophylaxis in patients with neutropenia	200 mg once daily	See note on impaired absorption below.
1 Duration of treatment should be adjusted according to clinical response. Impaired absorption in patients with AIDS and neutropenia may lead to low itraconazole blood concentrations and reduced efficacy. In such cases, monitoring of itraconazole blood levels is recommended, and dose may be increased to 200 mg twice daily if necessary.

Elderly patients.

The use of the drug in elderly patients is not recommended (see section "Special precautions").

Patients with renal function impairment.

Patients with hepatic function 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 drug in children is not recommended.

Overdose.

In general, adverse reactions reported in cases of overdose had a similar profile to those occurring during itraconazole treatment (see section "Adverse reactions"). In case of overdose, supportive measures should be taken. Itraconazole cannot be removed by hemodialysis. There is no specific antidote. For current recommendations on overdose management, contact a poison control center.

Adverse reactions.

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, angioedema, anaphylactic reactions.

Metabolism and nutrition disorders:

Rare – hypertriglyceridemia.

Nervous system disorders:

Common – headache.

Rare – paresthesia, hypoesthesia, dysgeusia, tremor.

Eye disorders:

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

Ear and labyrinth disorders:

Rare – temporary or permanent hearing loss*, tinnitus.

Cardiac disorders:

Rare – congestive heart failure*.

Respiratory system disorders:

Rare – dyspnea.

Gastrointestinal disorders:

Common – abdominal pain, nausea.

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

Rare – pancreatitis.

Hepatobiliary disorders:

Uncommon – liver function abnormalities.

Rare – severe hepatotoxicity (including several cases of severe acute liver failure with fatal outcome)*, hyperbilirubinemia.

Skin and subcutaneous tissue disorders:

Uncommon – urticaria, rash, pruritus.

Renal and urinary disorders:

Rare – polyuria.

Reproductive system and breast disorders:

Uncommon – menstrual disorders.

Rare – erectile dysfunction.

General disorders and administration site conditions:

Uncommon – edema.

Investigations:

Rare – increased blood creatine phosphokinase levels.

* See section "Special precautions for use".

List of specific adverse reactions.

The following adverse reactions associated with itraconazole use were reported during clinical studies of the 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 swelling, chest pain, fever, pain, fatigue, chills.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy 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, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer.

Marxans Pharma Ltd.

Manufacturer's address and site of operations.

Manufacturing site address:

Plot No. L-82, L-83, Verna Industrial Estate, Verna Goa, IN-403 722, India

Marketing Authorization Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.