gelatin capsule: azorubine (E 122), patent blue V (E 131), titanium dioxide (E 171), caramel (E 150), gelatin.
Dosage form
Capsules.
Main physicochemical properties: hard gelatin capsules with a pink cap and a brown body, containing spherical micropellets from white to almost white.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives.
ATX code J02A C02.
Pharmacological properties
Pharmacodynamics.
Itraconazole is a triazole derivative with a broad spectrum of activity.
Itraconazole inhibits the synthesis of ergosterol in fungal cells. Ergosterol is an important component of the fungal cell membrane, inhibition of its synthesis provides an antifungal effect.
For itraconazole, breakpoints have only been established for Candida spp. For superficial mycotic infections (CLSI M27-A2, breakpoints not established by EUCAST methodology). The CLSI breakpoints are as follows: susceptible ≤ 0.125; susceptible dose-dependent 0.25-0.5 and resistant ≥ 1 µg/ml. Breakpoints have not been established for mycelial fungi.
Itraconazole inhibits the growth of a wide range of fungi pathogenic to humans at concentrations usually ≤ 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, Coccidiodes 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 have shown resistance to itraconazole in vitro.
The main types of fungi that are not inhibited by itraconazole are zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., and Absidia spp.), Fusarium spp., Scedosporium proliferans, and Scopulariopsis spp.
Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. Mechanisms that have been described include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 that result in reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of a transporter that results in increased efflux of itraconazole from fungal cells (i.e., removal of itraconazole from its target). Cross-resistance among azoles has been observed within Candida species, but resistance to one member of the class does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Pharmacokinetics.
General pharmacokinetic characteristics.
Peak plasma concentrations of itraconazole are reached within 2 to 5 hours after oral administration. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after multiple administration. Steady-state concentrations are generally reached 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 that are almost undetectable in plasma within 7-14 days, depending on the dose and duration of treatment. The mean 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. Peak plasma concentrations of unchanged drug after oral administration of capsules are reached within 2-5 hours. Absolute bioavailability of itraconazole is 55%. Maximum bioavailability when administered orally is observed when the drug is administered immediately after a high-calorie meal. Absorption of itraconazole capsules is reduced in patients with reduced gastric acidity, patients taking drugs that suppress gastric acid secretion (H2-receptor antagonists, proton pump inhibitors), or in patients with achlorhydria caused by certain diseases (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interaction”). Absorption of itraconazole on an empty stomach in such patients increases if Funit® capsules are used with drinks with increased acidity (e.g. non-diet cola). When a single dose of 200 mg Funit® capsules is administered on an empty stomach with non-diet cola after administration of ranitidine, an H2-receptor antagonist, the absorption of itraconazole is comparable to that observed after administration of Funit® capsules alone.
The concentration of itraconazole after administration of capsules is lower than after administration of oral solution at the same dose (see section "Special instructions").
Itraconazole is largely bound to plasma proteins (99.8%), with albumin being the major binding component (99.6% for the hydroxymetabolite). It also has a high affinity for lipids. Only 0.2% of itraconazole remains unbound in the blood. 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 those in plasma. Accumulation of itraconazole in keratinous tissues, especially in the skin, was 4 times higher than that in plasma. Concentrations in cerebrospinal fluid are much lower than in blood plasma, but efficacy has been demonstrated against infections localized in the cerebrospinal fluid.
Biotransformation
Itraconazole is extensively metabolized in the liver to form a large number of metabolites. One of these metabolites is hydroxyitraconazole, which has comparable antifungal activity to itraconazole in vitro. Plasma concentrations of hydroxyitraconazole are approximately 2-fold higher than those of itraconazole.
According to in vitro studies, CYP3A4 is the main enzyme involved in the metabolism of itraconazole.
Breeding
Approximately 35% of itraconazole is excreted as inactive metabolites in the urine and approximately 54% in the feces within 1 week of a dose of the oral solution. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole after intravenous administration is less than 1% of the dose. Fecal excretion of unchanged drug varies from 3 to 18%.
Special categories of patients
Liver failure.
Itraconazole is primarily metabolized in the liver. A pharmacokinetic study using a single dose of 100 mg itraconazole (1 capsule of 100 mg) was conducted in 6 healthy subjects and 12 cirrhotic subjects. No clinically significant difference in AUC∞ was observed between the two groups. In cirrhotic subjects, a clinically significant decrease in mean Cmax (47%) and a 2-fold increase in the half-life of itraconazole (37±17 vs. 16±5 hours) were observed.
There are no data available on the long-term use of itraconazole in patients with cirrhosis.
Kidney failure.
Data on the use of oral itraconazole in patients with renal impairment are limited.
There are no data available on the long-term use of itraconazole in patients with renal impairment. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole.
Children.
Data on the use of oral itraconazole in children are limited.
Indication
Vulvovaginal candidiasis;
lichen planus;
dermatophytosis caused by itraconazole-sensitive pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), e.g. tinea pedis, inguinal tinea, tinea corporis, tinea corporis of the hands;
oropharyngeal candidiasis;
onychomycoses caused by dermatophytes and/or yeasts;
histoplasmosis;
systemic mycoses (in cases where first-line antifungal therapy cannot be used or in case of ineffectiveness of treatment with other antifungal drugs, which may be due to the existing pathology, insensitivity of the pathogen or toxicity of the drug):
aspergillosis and candidiasis;
Cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with cryptococcosis of the central nervous system;
maintenance therapy in patients with AIDS to prevent recurrence of an existing fungal infection.
Funit® can also be prescribed for the prevention of fungal infection in patients with prolonged neutropenia in cases where standard therapy is insufficient.
Contraindication
Funit® capsules are contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.
The simultaneous use of Funit® and CYP3A4 substrates is contraindicated (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”). These include:
Antibacterials for systemic use; antimycobacterials; antimycotic agents for systemic use
Isavuconazole
Anthelmintic and antiprotozoal agents
Halofantrine
Antihistamines for systemic use
Astemizole
Mizolastine
Terfenadine
Antineoplastic agents
Irinotecan
Venetoclax (in patients with chronic lymphocytic leukemia during the venetoclax initiation and dose titration phase)
Antiplatelet agents
Dabigatran
Ticagrelor
Antiviral agents for systemic use
Ombitasvir/paritaprevir/
ritonavir
(with or without dasabuvir)
Cardiovascular system (agents affecting the renin-angiotensin system; antihypertensives; beta-blockers; calcium channel blockers; cardiotherapy; diuretics)
Aliskiren
Eplerenone
Quinidine
Bepridil
Finerenone
Ranolazine
Disopyramide
Ivabradine
Sildenafil (pulmonary hypertension)
Dofetilide
Lercanidipine
Dronedarone
Nisoldipine
Gastrointestinal agents, including antidiarrheals, intestinal anti-inflammatory/anti-infectives; antiemetics; laxatives; agents used in functional gastrointestinal disorders
Cisapride
Domperidone
Naloxegol
Lipid-regulating drugs
Lovastatin
Lomitapide
Simvastatin
Psychoanaleptics; psycholeptics (e.g. antipsychotics, anxiolytics and hypnotic-sedatives)
Lurasidone
Pimozide
Sertindole
Midazolam (for oral use)
Quetiapine
Triazolam
Medications that affect 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 over)
Others
Colchicine (in patients with renal and hepatic impairment)
Eliglustat (in patients with CYP2D6 poor metabolizers (PMs), CYP2D6 intermediate metabolizers (IMs), or extensive metabolizers (EMs) taking a strong or moderate CYP2D6 inhibitor)
Funit® capsules are contraindicated in patients with ventricular dysfunction, such as congestive heart failure, or a history of congestive heart failure, except for the treatment of life-threatening infections (see section "Special warnings and precautions for use").
Funit® capsules should not be used during pregnancy, except for the treatment of conditions that threaten the life of the mother (see section “Use during pregnancy or breastfeeding”).
Women of reproductive age should use effective methods of contraception during treatment with Funit® capsules, as well as until the end of the menstrual cycle after the end of treatment.
Interaction with other medicinal products and other types of interactions
Itraconazole is primarily metabolized by cytochrome CYP3A4. Other drugs that are metabolized by this pathway or modify the activity of CYP3A4 may affect the pharmacokinetics of itraconazole. Itraconazole, in turn, may also affect the pharmacokinetics of other substances. Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, as well as an inhibitor of breast cancer resistance protein (BCRP). Itraconazole may alter the pharmacokinetics of other substances that share this metabolic pathway or protein transport pathways.
Examples of drugs that may affect itraconazole plasma concentrations are listed by drug class in Table 1. Examples of drugs whose plasma concentrations may be affected by itraconazole are listed in Table 2. Due to the number of interactions, potential changes in the safety or efficacy of interacting drugs are not considered. The prescribing information for the interacting drug should be consulted for further information.
The interactions described in Tables 1 and 2 are classified as contraindicated, not recommended, or should be used with caution with itraconazole, taking into account the degree of increase in concentration and the safety profile of the interacting drug. The potential for interactions of the listed drugs was assessed based on pharmacokinetic studies of itraconazole and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g., ketoconazole) and/or in vitro data:
Contraindicated: under no circumstances should it be used simultaneously with or within 2 weeks of the end of treatment with itraconazole.
Not recommended: The use of these drugs concomitantly and within 2 weeks after discontinuation of itraconazole treatment should be avoided unless the expected benefit of treatment outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be carefully monitored for signs or symptoms of increased or prolonged pharmacological effects of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor the level of itraconazole plasma concentrations.
Examples of drugs whose concentrations are increased when co-administered with itraconazole are listed in the table with the appropriate recommendations. However, the extent of the interaction may depend on the dose of itraconazole administered. A stronger interaction may occur at higher doses or at shorter dosing intervals. Extrapolation of the results to other dosing scenarios or different drugs should be done with caution.
After discontinuation of treatment, itraconazole concentrations decline to undetectable levels in plasma within 7-14 days, depending on the dose and duration of treatment. In patients with cirrhosis of the liver or in patients concomitantly taking CYP3A4 inhibitors, discontinuation of the drug should be gradual. This is especially true for drugs whose metabolism is affected by itraconazole.
Table 1
Drugs that may affect itraconazole plasma concentrations are presented by drug class.
Drugs (single oral dose unless otherwise specified) within the class
Expected/potential effect on itraconazole levels
(↑ = increase; ↔ = no change; ↓ = decrease)
Clinical commentary
(see above for more information)
Antibacterials for systemic use; antimycobacterials
Isoniazid
Although isoniazid has not been studied directly, it is likely to reduce itraconazole concentrations.
Not recommended
Rifampicin orally 600 mg once daily
Itraconazole AUC ↓
Not recommended
Rifabutin orally 300 mg once daily
Itraconazole Cmax ↓ 71%, AUC ↓ 74%
Not recommended
Ciprofloxacin orally 500 mg twice daily
Itraconazole Cmax ↑ 53%, AUC ↑ 82%
Use with caution.
Erythromycin 1 g
Itraconazole Cmax ↑ 44%, AUC ↑ 36%
Use with caution.
Clarithromycin orally 500 mg twice daily
Itraconazole Cmax ↑ 90%, AUC ↑ 92%
Use with caution.
Antiepileptic drugs
Carbamazepine, phenobarbital
Although these drugs have not been studied directly, they likely decrease itraconazole concentrations.
Not recommended
Phenytoin orally 300 mg once daily
Itraconazole 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 concentrations.
Use with caution.
Antiviral agents for systemic use
Ombitasvir/paritaprevir/
ritonavir (with or without dasabuvir)
Although these drugs have not been studied directly, they are expected to increase itraconazole concentrations.
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Contraindicated
Eletriptan, fentanyl
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Not recommended
Alfentanil, buprenorphine (IV and sublingual), cannabinoids, methadone, sufentanil
Although not directly studied, itraconazole may increase the 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; antimycotic agents for systemic use
Isavuconazole
Although not directly studied, itraconazole may increase the concentration of isavuconazole.
Contraindicated
Bedaquiline
Although not studied directly, itraconazole is likely to increase bedaquiline concentrations.
Not recommended
Rifabutin orally 300 mg once daily
Rifabutin, concentration ↑ (level unknown)
Not recommended
Clarithromycin orally 500 mg twice daily
Clarithromycin, concentration ↑
Use with caution.
Delamanid
Although not directly studied, itraconazole may increase delaminide concentrations.
Use with caution.
Antiepileptic drugs
Carbamazepine
Although not directly studied, itraconazole may increase the concentration of carbamazepine.
Not recommended
Anti-inflammatory and antirheumatic drugs
Meloxicam 15 mg
Meloxicam Cmax ↓ 64%, AUC ↓ 37%
Use with caution.
Anthelmintic; antiprotozoal
Halofantrine
Although not directly studied, itraconazole may increase halofantine concentrations.
Contraindicated
Artemether-lumefantrine, praziquantel
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Use with caution.
Quinine 300 mg
Quinine Cmax ↔, AUC ↑ 96%
Use with caution.
Antihistamines for systemic use
Astemizole, mizolastine, terfenadine
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Contraindicated
Ebastine 20 mg
Ebastine Cmax ↑ 2.5 times, AUC ↑ 6.2 times
Carabastin Cmax ↔, AUC ↑ 3.1 times
Not recommended
Bilastine, rupatadine
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Use with caution.
Antineoplastic agents
Irinotecan
Although itraconazole has not been directly studied, it is likely that itraconazole increases the concentration of irinotecan and its active metabolite.
Contraindicated
Venetoclax
Although itraconazole has not been directly studied, it is likely that itraconazole increases venetoclax concentrations.
Contraindicated in patients with chronic lymphocytic leukemia during the initiation and titration phase of venetoclax. Otherwise not recommended unless benefits outweigh risks. Refer to venetoclax prescribing information.
Although itraconazole has not been studied directly, itraconazole is likely to increase the concentrations of these drugs, with the exception of cabazitaxel and regorafenib. There is no statistically significant change in cabazitaxel exposure, but there is a large variability in the results. The AUC of regorafenib is expected to decrease (based on the active moiety estimate).
Although not directly studied, itraconazole is likely to increase the concentration of nasally administered fluticasone.
Use with caution.
Diabetes medications
Repaglinide 0.25 mg
Repaglinide Cmax ↑ 47%, AUC ↑ 41%
Use with caution.
Saxagliptin
Although itraconazole has not been directly studied, itraconazole may increase saxagliptin concentrations.
Use with caution.
Gastrointestinal agents, including antidiarrheals, intestinal anti-inflammatory/anti-infectives; antiemetics; laxatives; agents used in functional gastrointestinal disorders
Cisapride, naloxegol
Although not directly studied, itraconazole may increase the concentrations of these drugs.
Contraindicated
Domperidone 20 mg
Domperidone Cmax ↑ 2.7 times, AUC ↑ 3.2 times
Contraindicated
Aprepitant, loperamide, netupitant
Although itraconazole has not been directly studied, it is likely that itraconazole increases the concentration of aprepitant.
Use with caution.
Immunosuppressants
Sirolimus (rapamycin)
Although itraconazole has not been directly studied, itraconazole may increase sirolimus concentrations.
Not recommended
Cyclosporine, tacrolimus
Although itraconazole has not been directly studied, itraconazole may increase cyclosporine concentrations.
Use with caution.
Tacrolimus IV 0.03 mg/kg once daily
Use with caution.
Lipid-regulating drugs
Lomitapide
Although itraconazole has not been directly studied, it may increase lomitapide concentrations.
