Funit®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUNIT® (FUNIT)

Composition:

Active substance: itraconazole;

1 capsule contains 100 mg of itraconazole;

Excipients: hydroxypropylmethylcellulose, polyethylene glycol 6000;

Neutral micropellets: spherical sugar, maize starch;

Gelatin capsule: azorubine (E 122), patent blue V (E 131), titanium dioxide (E 171), caramel (E 150), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules with a pink cap and a brown body, containing spherical micropellets ranging from white to almost white.

Pharmacotherapeutic group.

Antifungal agents for systemic use. Triazole derivatives.

ATC code J02A C02.

Pharmacological Properties.

Pharmacodynamics.

Itraconazole is a triazole derivative with a broad spectrum of activity.

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.

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

Itraconazole inhibits the growth of a wide range of fungi pathogenic to humans at concentrations typically ≤ 1 µg/mL. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis, and C. krusei; Cryptococcus neoformans; Malassezia spp.; Trichosporon spp.; Geotrichum spp.), Aspergillus spp., Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis; Pseudallescheria boydii; Penicillium marneffei; and other yeast and mold species. Candida krusei, Candida glabrata, and Candida tropicalis are generally the least susceptible Candida species, and some isolates exhibit in vitro resistance to itraconazole.

The main 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. Mechanisms described include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of efflux transporters, resulting in increased export of itraconazole from fungal cells (i.e., removal of itraconazole from its target site). Cross-resistance among azole-class agents has been observed within Candida species; however, resistance to one azole does not necessarily imply resistance to others. 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 with repeated dosing. Steady-state concentrations are generally achieved within 15 days, with Cmax values of 0.5 µg/mL, 1.1 µg/mL, and 2.0 µg/mL after 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34–42 hours after multiple doses. After discontinuation of treatment, itraconazole concentrations decline to levels nearly undetectable in plasma within 7–14 days, depending on the dose and duration of therapy. The mean plasma clearance of itraconazole after intravenous administration is 278 mL/min. Due to saturable hepatic metabolism at higher doses, the clearance of itraconazole decreases.

Absorption.

Itraconazole is rapidly absorbed after oral administration. Maximum plasma concentrations of unchanged drug are achieved within 2–5 hours after oral capsule administration. Absolute bioavailability of itraconazole is 55%. Maximum bioavailability is observed when the drug is administered immediately after a high-calorie meal. Absorption of itraconazole capsules is reduced in patients with decreased gastric acidity, patients taking acid-suppressing agents (H2-receptor antagonists, proton pump inhibitors), or patients with achlorhydria due to certain diseases (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Absorption of itraconazole on an empty stomach in such patients is increased if Funite® capsules are taken with acidic beverages (e.g., non-diet cola). When a single 200 mg dose of Funite® capsules is administered on an empty stomach with non-diet cola following ranitidine (an H2-receptor antagonist), absorption of itraconazole is comparable to that observed after administration of Funite® capsules alone.

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

Biological transformation.

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

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

Elimination.

Approximately 35% of itraconazole is excreted as inactive metabolites in urine and about 54% in feces within one week after administration of the oral solution dose. Renal excretion of unchanged itraconazole and active metabolite hydroxy-itraconazole 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 subjects and 12 patients with cirrhosis. No clinically significant difference in AUC∞ was observed between the two groups. In cirrhotic patients, a clinically significant reduction in mean Cmax (47%) and a doubling of the elimination half-life (37±17 vs. 16±5 hours) were observed.

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 impaired renal function are limited.

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

Pediatric population.

Data on the use of oral itraconazole in children are limited.

Clinical characteristics.

Indications.

• Vulvovaginal candidiasis;

• Lichen planus;

• Dermatomycoses caused by itraconazole-sensitive causative agents (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), for example, tinea pedis, tinea cruris, tinea corporis, tinea manuum;

• Oropharyngeal candidiasis;

• Onychomycoses caused by dermatophytes and/or yeasts;

• Histoplasmosis;

• Systemic mycoses (in cases 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 patients with AIDS to prevent recurrence of existing fungal infection.

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

Contraindications.

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

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

Analgesics, anesthetics
Ergoline alkaloids (e.g., dihydroergotamine, ergometrine, ergotamine, methylergometrine)
Antibacterial agents for systemic use; antimycobacterial agents; antifungal agents for systemic use
Isavuconazole
Anthelmintic and antiprotozoal agents
Halofantrine
Systemic antihistamines
Astemizole	Mizolastine	Terfenadine
Antineoplastic agents
Irinotecan	Venetoclax (in patients with chronic lymphocytic leukemia during the initiation and dose-titration phase of venetoclax)
Antiplatelet agents
Dabigatran	Ticagrelor
Systemic antiviral agents
Ombitasvir/paritaprevir/ ritonavir (with or without dasabuvir)
Cardiovascular system (agents affecting 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; laxatives; agents used in functional gastrointestinal disorders
Cisapride	Domperidone	Naloxegol
Lipid-regulating drugs
Lovastatin	Lomitapide	Simvastatin
Psychoanaleptics; psycholeptics (e.g., antipsychotics, anxiolytics, and hypnotics-sedatives)
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)
Others
Colchicine (in patients with renal or hepatic impairment)	Eliglustat (in CYP2D6 poor metabolizers (PM), intermediate metabolizers (IM), or extensive metabolizers (EMs) who are taking a strong or moderate CYP2D6 inhibitor)

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

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

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

Interaction with other medicinal products and other types of interactions.

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

Examples of drugs that may affect plasma concentrations of itraconazole are listed by drug classes in Table 1. Examples of drugs whose plasma concentrations may be affected by itraconazole are presented in Table 2. Due to the number of interactions, potential changes in safety or efficacy of interacting drugs are not fully accounted for. It is necessary to refer to prescribing information for the interacting drug for additional details.

Interactions described in Tables 1 and 2 are classified as contraindicated, not recommended, or requiring cautious use with itraconazole, depending on the degree of concentration increase and the safety profile of the interacting drug. The potential for interaction of the listed drugs was assessed based on pharmacokinetic studies of itraconazole and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g., ketoconazole) and/or in vitro data:

• Contraindicated: Do not use concomitantly or within 2 weeks after discontinuation of itraconazole treatment.
• Not recommended: Concomitant use of these medicinal products and for 2 weeks after stopping itraconazole treatment should be avoided, except when the expected benefit outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, patients should be closely monitored for signs or symptoms of increased or prolonged pharmacological effect of itraconazole, and the dose of itraconazole should be reduced if necessary. Therapeutic drug monitoring of itraconazole plasma concentration is recommended.
• Use with caution: Careful monitoring is recommended when used concomitantly with itraconazole. Patients should be closely observed for signs or symptoms of increased or prolonged pharmacological effects of itraconazole or adverse reactions, and the dose of itraconazole should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

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

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

Table 1

Drugs that may affect plasma concentrations of itraconazole, listed by drug classes

Medicinal products (single oral dose unless otherwise stated) within class	Expected/potential effect on itraconazole levels (↑ = increase; ↔ = no change; ↓ = decrease)	Clinical comment (see above for additional information)
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
Antiepileptics
Carbamazepine, phenobarbital	Although these agents 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
Antivirals for systemic use
Ombitasvir/paritaprevir/ ritonavir (with or without dasabuvir)	Although these agents 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 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, they are expected to increase itraconazole concentration.	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 is likely to increase itraconazole concentration.	Use with caution
Agents 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, rabeprazole)	Itaconazole Cmax ↓, AUC ↓	Use with caution
Agents affecting the respiratory system
Lumacaftor/ivacaftor oral 200/250 mg twice daily	Itaconazole concentration ↓	Not recommended
Others
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

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

Medicinal products (single oral dose unless otherwise stated) within class	Expected/potential effect on itraconazole levels (↑ = increase; ↔ = no change; ↓ = decrease)	Clinical comment (see above for additional information)
Analgesics; anaesthetics
Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)	Although not directly studied, itraconazole may increase concentrations of these drugs.	Contraindicated
Eletriptan, fentanyl	Although not directly studied, itraconazole may increase concentrations of these drugs.	Not recommended
Alfentanil, buprenorphine (IV and sublingual), cannabinoids, methadone, sufentanil	Although not directly studied, itraconazole 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 IV 0.1 mg/kg	Oxycodone IV: AUC ↑ 51%	Use with caution
Antibacterials for systemic use; antimycobacterials; antifungals for systemic use
Isavuconazole	Although not directly studied, itraconazole may increase isavuconazole concentrations.	Contraindicated
Bedaquiline	Although not directly studied, itraconazole is likely to increase bedaquiline concentrations.	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 not directly studied, itraconazole may increase delamanid concentrations.	Use with caution
Antiepileptics
Carbamazepine	Although not directly studied, itraconazole may increase carbamazepine concentrations.	Not recommended
Anti-inflammatory and antirheumatic agents
Meloxicam 15 mg	Meloxicam Cmax ↓ 64%, AUC ↓ 37%	Use with caution
Antihelminthics; antiprotozoals
Halofantrine	Although not directly studied, itraconazole may increase halofantrine concentrations.	Contraindicated
Artemether-lumefantrine, praziquantel	Although not directly studied, itraconazole 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 not directly studied, itraconazole may increase concentrations of these drugs.	Contraindicated
Ebastine 20 mg	Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2-fold Carb-ebastine Cmax ↔, AUC ↑ 3.1-fold	Not recommended
Bilastine, rupatadine	Although not directly studied, itraconazole may increase concentrations of these drugs.	Use with caution
Antineoplastics
Irinotecan	Although not directly studied, itraconazole is likely to increase concentrations of irinotecan and its active metabolite.	Contraindicated
Venetoclax	Although not directly studied, itraconazole is likely to increase venetoclax concentrations.	Contraindicated in patients with chronic lymphocytic leukaemia during the initiation and 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 not directly studied, itraconazole is likely to increase concentrations of these drugs, except for cabazitaxel and regorafenib. No statistically significant change 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, tretinoin (oral)	Although not directly studied, itraconazole 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
Pretomanid 250 mg	Pretomanid 250 mg Cmax ↑ 17%, AUC ↑ 91%	Use with caution
Antithrombotics
Dabigatran, ticagrelor	Although not directly studied, itraconazole may increase concentrations of these drugs.	Contraindicated
Apixaban, edoxaban, rivaroxaban, vorapaxar	Although not directly studied, itraconazole may increase concentrations of these drugs.	Not recommended
Cilostazol, coumarins (e.g. warfarin)	Although not directly studied, itraconazole may increase concentrations of these drugs.	Use with caution
Systemic antivirals
Ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)	Itraconazole may increase paritaprevir concentrations.	Contraindicated
Elbasvir/grazoprevir, simeprevir, tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF)	Although not directly studied, itraconazole may increase concentrations of these drugs.	Not recommended
Cobicistat, elvitegravir (boosted with ritonavir), glecaprevir/pibrentasvir, maraviroc, ritonavir, saquinavir	Although not directly studied, itraconazole 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 affecting the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiotonics; diuretics)
Bepridil, disopyramide, dofetilide, dronedarone, eplerenone, finerenone, ivabradine, lercanidipine, nicardipine, ranolazine, sildenafil (pulmonary hypertension)	Although not directly studied, itraconazole 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 not directly studied, itraconazole may increase concentrations of these drugs.	Not recommended
Bosentan, diltiazem, guanfacine, other dihydropyridines (e.g. amlodipine, isradipine, nifedipine, nimodipine), verapamil	Although not directly studied, itraconazole is likely to increase bosentan concentrations.	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 not directly studied, itraconazole is likely to increase salmeterol and active metabolite of ciclesonide concentrations.	Not recommended
Budesonide INH 1 mg subcutaneously	Budesonide INH Cmax ↑ 65%, AUC ↑ 4.2-fold; budesonide (other formulations) concentration ↑	Use with caution
Dexamethasone IV 5 mg Dexamethasone oral 4.5 mg	Dexamethasone IV: Cmax ↔, AUC ↑ 3.3-fold Dexamethasone oral: Cmax ↑ 69%, AUC ↑ 3.7-fold	Use with caution
Fluticasone INH 1 mg twice daily	Fluticasone INH concentration ↑	Use with caution
Methylprednisolone 16 mg	Methylprednisolone oral Cmax ↑ 92%, AUC ↑ 3.9-fold Methylprednisolone IV AUC ↑ 2.6-fold	Use with caution
Fluticasone nasal	Although not directly studied, itraconazole is likely to increase nasal fluticasone concentrations.	Use with caution
Antidiabetic agents
Repaglinide 0.25 mg	Repaglinide Cmax ↑ 47%, AUC ↑ 41%	Use with caution
Saxagliptin	Although not directly studied, itraconazole may increase saxagliptin concentrations.	Use with caution
Gastrointestinal agents, including antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents; antiemetics; laxatives; agents used in functional gastrointestinal disorders
Cisapride, naloxegol	Although not directly studied, itraconazole may increase concentrations of these drugs.	Contraindicated
Domperidone 20 mg	Domperidone Cmax ↑ 2.7-fold, AUC ↑ 3.2-fold	Contraindicated
Aprepitant, loperamide, netupitant	Although not directly studied, itraconazole is likely to increase aprepitant concentrations.	Use with caution
Immunosuppressants
Sirolimus (rapamycin)	Although not directly studied, itraconazole may increase sirolimus concentrations.	Not recommended
Cyclosporine, tacrolimus	Although not directly studied, itraconazole may increase cyclosporine concentrations.	Use with caution
Tacrolimus IV 0.03 mg/kg once daily	Tacrolimus IV concentration ↑	Use with caution
Lipid-regulating medicines
Lomitapide	Although not directly studied, itraconazole 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 ↔ to ↑2.5-fold, AUC ↑ 40% to 3-fold	Not recommended
Psychoanaleptics; psycholeptics (e.g. antipsychotics, anxiolytics and hypnotics-sedatives)
Loxapine, pimozide, quetiapine, sertindole	Although not directly studied, itraconazole 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
Brotizolam 0.5 mg	Brotizolam Cmax ↔, AUC ↑ 2.6-fold	Use with caution
Buspirone 10 mg	Buspirone Cmax ↑ 13.4-fold, AUC ↑ 19.2-fold	Use with caution
Midazolam (IV) 7.5 mg	Midazolam (IV) 7.5 mg: concentration ↑; although not directly studied, itraconazole is likely to increase midazolam concentrations after oral administration.	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 not directly studied, itraconazole may increase concentrations of these drugs.	Use with caution
Respiratory system: other respiratory products
Lumacaftor/ivacaftor oral 200/250 mg twice daily	Ivacaftor Cmax ↑ 3.6-fold, AUC ↑ 4.3-fold Lumacaftor Cmax ↔, AUC ↔	Not recommended
Ivacaftor	Although not directly studied, itraconazole is likely to increase ivacaftor concentrations.	Use with caution
Sex hormones and modulators of the genital system; other gynaecological agents
Cabergoline, dienogest, ulipristal	Although not directly studied, itraconazole may increase concentrations of these drugs.	Use with caution
Urologicals
Avanafil, dapoxetine, darifenacin	Although not directly studied, itraconazole may increase concentrations of these drugs.	Contraindicated
Fesoterodine	Although not directly studied, itraconazole is likely to increase concentrations of active metabolites 5-hydroxymethyl-tolterodine.	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 not directly studied, itraconazole may increase solifenacin concentrations.	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 not directly studied, itraconazole may increase vardenafil concentrations.	Contraindicated in patients over 75 years; otherwise not recommended.
Alfuzosin, silodosin, tadalafil (erectile dysfunction and benign prostatic hyperplasia), tamsulosin, tolterodine	Although not directly studied, itraconazole may increase concentrations of these drugs.	Not recommended
Dutasteride, imidafenacin, sildenafil (erectile dysfunction)	Although not directly studied, itraconazole may increase concentrations of these drugs.	Use with caution
Oxybutynin 5 mg	Oxybutynin Cmax ↑ 2-fold, AUC ↑ 2-fold N-desethyloxybutynin Cmax ↔, AUC ↔ After transdermal administration: although not directly studied, itraconazole is likely to increase transdermal oxybutynin concentrations.	Use with caution
Others
Colchicine	Although not directly studied, itraconazole may increase colchicine concentrations.	Contraindicated in patients with renal or hepatic impairment. Not recommended in other patients.
Eliglustat	Itraconazole is expected to increase eliglustat concentrations, although not directly studied.	Contraindicated in poor metabolizers (PM) of CYP2D6. Contraindicated in intermediate (IM) or extensive metabolizers (EM) taking strong or moderate CYP2D6 inhibitors. Use with caution in CYP2D6 IM and EM. For EM with mild hepatic impairment, consider eliglustat dose of 84 mg/day.
Cinacalcet	Although not directly studied, itraconazole may increase cinacalcet concentrations.	Use with caution

Special precautions for use.

Cross-sensitivity.

There are no data on cross-sensitivity between itraconazole and other azole antifungal agents. Caution should be exercised when prescribing Funit® capsules to patients who are hypersensitive to other azoles.

Effect on the heart.

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

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

The drug should not be administered to patients with existing congestive heart failure or a history of congestive heart failure, except when the expected benefit clearly outweighs the potential risk. In individual assessment of benefit-risk ratio, the following factors should be considered: severity of the indication, dosing regimen and duration of treatment (total daily dose), and individual risk factors for developing congestive heart failure. These risk factors include pre-existing cardiac conditions such as ischemic heart disease or valvular disease; severe pulmonary diseases such as obstructive lung disease; renal impairment or other conditions associated with edema. Such patients should be informed about the signs and symptoms of congestive heart failure, treatment should be administered cautiously, and symptoms of heart failure should be monitored. If such symptoms occur during treatment, Funit® should be discontinued immediately.

Calcium channel blockers may have a negative inotropic effect, which may be enhanced by the same effect of itraconazole. In addition, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when co-administering itraconazole and 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 outcomes, has been very rarely reported with Funit® capsules. Most of these cases occurred in patients with a history of liver disease, who were treated for systemic indications, had other serious underlying conditions, 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 Funit®. Patients should be warned to seek immediate medical attention if signs or symptoms of hepatitis occur, such as anorexia, nausea, vomiting, increased fatigue, abdominal pain, or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed.

Data on the use of oral itraconazole in patients with hepatic impairment are limited. This medicinal product should be used with caution in this patient population. Close monitoring of patients with impaired liver function who are taking itraconazole is recommended. When making treatment decisions involving 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 (see section "Pharmacokinetics").

Treatment with Funit® should be initiated only in patients with elevated liver enzymes, active liver disease, or signs of hepatotoxicity from other drugs if the expected benefit outweighs the risk of liver injury. In such cases, monitoring of liver function is required in patients with active liver disease or signs of hepatotoxicity from other drugs (see section "Pharmacokinetics").

Reduced gastric acidity.

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

Paediatric population.

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

Elderly patients.

Clinical data on the use of Funit® capsules in elderly patients are limited. Funit® capsules 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 the higher frequency of decreased liver, kidney, or cardiac function, as well as concomitant diseases or other medicinal products.

Renal impairment.

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

Hearing loss.

Cases of temporary or permanent hearing loss have been reported in patients taking itraconazole. In some cases, hearing loss occurred during concomitant use with quinidine, which is contraindicated (see section "Interaction with other medicinal products and other forms of interaction"). Hearing usually recovers after discontinuation of Funit®, 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 Funit® capsules may be reduced.

Patients with life-threatening systemic fungal infections.

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

Patients with AIDS.

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, the physician should evaluate the need for maintenance therapy.

Neuropathy.

If neuropathy occurs related to the use of Funit® capsules, treatment should be discontinued.

Cystic fibrosis.

Variable plasma levels of itraconazole have been observed in patients with cystic fibrosis after oral administration at a dose of 2.5 mg/kg twice daily. Steady-state concentrations > 250 ng/mL were achieved in approximately 50% of patients aged 16 years and older, but in none of the patients under 16 years of age. If a patient does not show a clinical response to Funit® capsules, consideration should be given to switching to alternative therapy.

Carbohydrate metabolism disorders.

This medicinal product is contraindicated in patients with rare hereditary disorders 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, a susceptibility test should be performed before initiating treatment with Funit® capsules.

Interchangeability.

Interchangeability between itraconazole capsules and oral solution is not recommended. This is because, when the same dose is administered, drug exposure is higher with the oral solution than with the capsules.

Interaction potential.

Concomitant use of itraconazole and certain medicinal products may lead to changes in the efficacy of itraconazole and/or the concomitantly administered drug, adverse reactions that may be life-threatening, and/or sudden fatal outcomes. Medicinal products that are contraindicated, not recommended, or recommended for use with caution together with itraconazole are listed in the sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Use during pregnancy or breastfeeding.

Pregnancy.

Funit® should not be prescribed during pregnancy except in life-threatening systemic mycoses when the potential benefit to the mother outweighs the risk of adverse effects on the fetus (see section "Contraindications").

In animal studies, itraconazole showed reproductive toxicity.

Data on the use of Funit® during pregnancy are limited. During the post-marketing period, cases of developmental abnormalities have been reported. These cases included skeletal, genitourinary, cardiovascular, and ocular malformations, as well as chromosomal abnormalities and multiple congenital anomalies. A causal relationship with Funit® capsules has not been established.

Epidemiological data on the use of Funit® during the first trimester of pregnancy (mainly in patients using 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 Funit® capsules should use reliable contraceptive methods throughout the treatment course and until the first menstrual period after completion of treatment.

Breastfeeding.

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 Funit® treatment for the mother. In cases of doubt, the woman should discontinue breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Studies on the influence 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 "Undesirable effects") should be considered, which may lead to adverse outcomes while driving or operating machinery.

Administration and Dosage.

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

The treatment regimens for adults for each indication are as follows:

Indications	Dosage	Duration
Vulvovaginal candidiasis	200 mg twice daily	1 day
Tinea versicolor	200 mg once daily	7 days
Crural dermatomycosis, tinea corporis	100 mg once daily	15 days
	200 mg once daily	7 days
Tinea pedis, tinea manuum	100 mg once daily	30 days
Oropharyngeal candidiasis	100 mg once daily	15 days
The dose should be increased to 200 mg once daily for 15 days in patients with neutropenia or AIDS due to impaired absorption of the drug in these patients.
Onychomycosis (infection of toenail plates, with or without involvement of fingernails)	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 infection therapy. This is due to the fact that itraconazole elimination from skin, nail, and mucosal tissues is slower than from blood plasma.

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

Systemic mycoses
Indications	Dosage	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 instructions").
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 blood itraconazole levels is recommended, and dose increase to 200 mg twice daily may be necessary.

Elderly patients.

The use of Funit® in elderly patients is not recommended (see section *«*Special precautions and warnings»).

Patients with renal impairment.

The bioavailability of the drug may be reduced in patients with renal insufficiency; dose adjustment should be considered (see section «Special precautions and warnings»).

Patients with hepatic impairment.

Itraconazole is predominantly metabolized in the liver. The terminal half-life of itraconazole is somewhat prolonged in patients with liver cirrhosis. Oral bioavailability is slightly reduced in patients with cirrhosis. Dose adjustment should be considered (see section «Special precautions and warnings»).

Children.

The use of Funit® 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. If justified, activated charcoal may be administered. Itraconazole cannot be removed by hemodialysis. There is no specific antidote.

Side effects

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

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

The adverse reactions listed below are grouped by system organ class, with terms within each class listed by frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

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.

Eye disorders:

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

Ear and labyrinth disorders:

• Rare – transient or permanent hearing loss, tinnitus.

Cardiac disorders:

• Not known – 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 resulting in death)*, 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;
• Not known – erectile dysfunction.

General disorders and administration site conditions:

• Uncommon – edema.

Investigations:

• Rare – increased blood creatine phosphokinase.

* See section "Special warnings and precautions for use".

Description of selected adverse reactions.

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

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

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

Psychiatric disorders: confusion.

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

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

Vascular disorders: hypertension, hypotension.

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

Gastrointestinal disorders: gastrointestinal disorders.

Hepatobiliary disorders: liver failure*, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

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

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

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

Paediatric population.

The safety of itraconazole capsules was evaluated in 165 paediatric patients aged 1 to 17 years enrolled in 14 clinical trials (4 double-blind, placebo-controlled trials; 9 open-label trials; 1 trial with an open phase followed by a double-blind phase). These patients received at least one dose of itraconazole capsules for treatment of fungal infections, and safety data were collected.

Based on pooled safety data from these clinical trials, the most commonly reported adverse reactions in children were: headache (3.0%), vomiting (3.0%), abdominal pain (2.4%), diarrhea (2.4%), liver function abnormalities (1.2%), hypotension (1.2%), nausea (1.2%), and urticaria (1.2%). Overall, the adverse reaction profile is similar to that in adults, although the frequency of occurrence is higher in children.

Shelf life. 3 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 ºC.

Keep out of reach of children.

Packaging.

4 capsules in a blister pack. 1 blister pack in a cardboard box.

5 capsules in a blister pack. 3 or 6 blister packs in a cardboard box.

15 capsules in a blister pack. 1 or 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Address of manufacturer and location of operations.

Sankaklar District, Eskisehir Yolu 299, 81100 Duzce, Turkey.