Itraconazole capsules 100 mg, 42 pcs.

Composition

Each capsule contains Itraconazole pellets (22%) – 0.460 g.

Composition of pellets:

Active ingredient: itraconazole-0.100 g;

excipients: hypromellose (hydroxypropylmethylcellulose E-5) – 0.1472 g, butylmethacrylate, dimethylaminoethylmethacrylate and methyl methacrylate copolymer [1:2:1] (eudragit E-100) – 0.0046 g, sucrose (sugar) – 0.2070 g.

Capsule shell composition: body: gelatin, titanium dioxide (E 171), azorubin (carmoisine) E 122; cap: gelatin, titanium dioxide (E 171), indigo carmine-F D & C Blue 2 (E 132).

Pharmacological action

Pharmacotherapeutic group: antifungal agent.

ATX code: J02AC 02

Pharmacological properties

Pharmacodynamics

Itraconazole is a synthetic broad-spectrum antifungal agent derived from triazole. The mechanism of action of itraconazole is to inhibit the biosynthesis of ergosterol – the main component of the fungal cell membrane involved in maintaining the structural integrity of the membrane. Violation of ergosterol synthesis leads to changes in membrane permeability and cell lysis, which causes the antifungal effect of the drug.

Itraconazole is active against fungal infections:

with dermatophytes (Trichophyton spp., Microsporum spp. Epidermophyton floccosum);

– yeast-like fungi (Candida spp. including C. albicans, C. tropicalis, C. parapsilosis, C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp. Geotrichum spp. ); Aspergillus spp. ; Histoplasma spp., including H. capsulatum; Responsible brasiliensis; Sporothrix schenckii; Fonsecaea spp. ; Cladosporium spp. ; Blastomyces dermatitidis; Coccidiodes immitis, Pseudallescheria boydii; Penicillium marneffei, and many others.

Candida krusei, Candida glabrata and Candida tropicalis are the least sensitive Candida species to itraconazole.

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

Resistance to azoles develops slowly and is often the result of several genetic mutations. The described mechanisms of resistance development include overexpression of the ERG11 gene encoding the 14α-demethylase enzyme, which is the main target of azoles, and point mutations of ERG11, which lead to a decrease in binding of enzymes to azoles and/or activation of transport systems, which leads to an increase in azole excretion. Cross-resistance of Candida spp. to azole group drugs was observed, although resistance to one drug of this group does not necessarily mean the presence of resistance to other azole group drugs. Itraconazole-resistant strains of Aspergillus fumigates have been reported.

Pharmacokinetics

Due to non-linear pharmacokinetics, itraconazole accumulates in the blood plasma with repeated administration. The steady-state concentration (_ss) of itraconazole is usually reached within about 15 days, with the maximum concentration (cmax) of itraconazole and AUC (area under the concentration-time curve) being 4-7 times higher with multiple doses than with a single dose. The maximum steady-state plasma concentration of itraconazole (_cvmax) is about 2 mcg / ml when 200 mg of itraconazole is administered once a day. The final half-life (T_1/2) is usually 16-28 hours for a single dose and 34-42 hours for multiple doses. The concentration of itraconazole in the blood plasma decreases to an almost undetectable value within 7-14 days after discontinuation of therapy, depending on the prescribed dose and duration of treatment. Clearance of itraconazole decreases at higher doses due to saturation of the pathways of its metabolism in the liver.

Absorption rate

Itraconazole is rapidly absorbed after oral administration. C_ssmax of unchanged itraconazole in plasma is reached within 2-5 hours after oral administration. The absolute bioavailability (F) of itraconazole after oral administration is about 55%. When administered orally, the maximum dose of itraconazole is observed when taking capsules immediately after a meal.

Absorption of itraconazole capsules is reduced in patients with low gastric acid content, for example, when taking drugs that suppress the secretion of hydrochloric acid in the stomach (such as H2-histamine receptor antagonists, proton pump inhibitors), or in patients with achlorhydria on the background of various diseases. The absorption of itraconazole on an empty stomach in such patients increases when taking the drug simultaneously with acidic drinks (such as non-dietary cola). Absorption of itraconazole remains unchanged when taking the drug at a dose of 200 mg once on an empty stomach together with non-dietary cola after preliminary administration of the H2-histamine receptor antagonist ranitidine.

The exposure of itraconazole is lower when taking itraconazole capsules compared to the exposure of itraconazole when taking the same dose as an oral solution.

Distribution

Itraconazole binds 99.8% to plasma proteins, mainly to albumin (hydroxyitraconazole binds to albumin by 99.6%). An affinity for lipids was also noted. Only 0.2% of itraconazole remains unbound in the plasma. Apparent volume of distribution (Vd) >700 l, which indicates a significant distribution in the tissues. Concentrations in the lungs, kidneys, bones, stomach, spleen and muscles are 2-3 times higher than the corresponding plasma concentrations, while the concentration of the drug in keratin-containing tissues, especially in the skin, is approximately 4 times higher than the plasma concentration. The concentration in the cerebrospinal fluid is significantly lower than in the blood plasma, however, the effectiveness of itraconazole against infectious agents present in the cerebrospinal fluid has been demonstrated.

Metabolism

As shown in in vitro studies, CYP3A4 is the main isoenzyme involved in the metabolism of itraconazole. Itraconazole undergoes active metabolism in the liver with the formation of many metabolites. The main metabolite is hydroxyitraconazole, which in vitro has antifungal activity comparable to itraconazole. Plasma concentrations of hydroxyitraconazole are approximately 2 times higher than those of itraconazole.

Excretion

Itraconazole is mainly excreted in the form of inactive metabolites in the urine (35%) and feces (54%) within one week after taking the oral solution. Renal excretion of itraconazole and its active metabolite hydroxyitraconazole is less than 1% of the intravenous dose. Based on the results of studying the pharmacokinetics of the 14C-labeled drug after oral administration, the excretion of unchanged itraconazole in the faeces varies from 3% to 18% of the dose taken.

Since the redistribution of itraconazole from keratin-containing tissues is insignificant, the elimination of itraconazole from these tissues is associated with the regeneration of the epidermis. Unlike blood plasma, the concentration of itraconazole in the skin persists for 2 to 4 weeks after the end of the 4-week treatment, and the concentration in nail keratin, where itraconazole can be detected as early as 1 week after the start of treatment, persists for at least 6 months after the end of the 3-month course of treatment.

Special patient categories:

Impaired liver function. Itraconazole is primarily metabolized in the liver. The pharmacokinetics study compared the pharmacokinetic parameters of patients with cirrhosis of the liver and healthy volunteers. In patients with cirrhosis of the liver, a single dose of 100 mg of itraconazole showed a significantly lower mean plasma cmax (47%) than in healthy patients. The average T_1/2at a single dose was increased in patients with cirrhosis of the liver and was 37±17 hours compared to 16±5 hours for healthy volunteers. Mean itraconazole exposure (AUC) was similar in patients with cirrhosis of the liver and in healthy volunteers. There are no data on the long-term use of itraconazole in patients with cirrhosis of the liver (see sections “Dosage and administration” and “Special instructions”).

Impaired renal function. Data on the oral use of itraconazole for the treatment of patients with impaired renal function are limited. In uremic patients with an average creatinineclearance of 13 ml/min x 1.73 m2, the systemic exposure to itraconazole (AUC) was slightly lower than in the general population. There was no significant effect of hemodialysis or prolonged outpatient peritoneal dialysis on the pharmacokinetics_{of itraconazole (tmax}, cmax, and AUC _{0-8 h}).

After a single intravenous administration of the drug, the final T_{1/2 of} itraconazole in patients with insignificant (defined in the study as Kk 50-79 ml / min), moderate (Kk 20-49 ml / min) or severe renal impairment (Kk Total exposure to itraconazole, based on the AUC score, was reduced in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, compared to patients with no impaired renal function.

Data on the long-term use of itraconazole in patients with impaired renal function are not available. Dialysis treatment does not affect T_1/2or clearance of itraconazole or hydroxyitraconazole.

Children. Data on the pharmacokinetics of itraconazole in paediatric patients are limited. Clinical pharmacokinetic studies in children and adolescents aged 5 months to 17 years were conducted with the use of itraconazole in capsules, oral solution and intravenous solution. Individual doses of the drug in the form of capsules and oral solution varied from 1.5 to 12.5 mg / kg / day when taken 1 or 2 times a day. When taking itraconazole at the same daily dose 2 times a day compared to taking 1 time a day_{, cmax} and cmin were comparable to those in adult patients when taking itraconazole 1 time a day. There were no significant age-related differences in the AUC of itraconazole and its total clearance; in rare cases, there was a slight relationship between the age of patients and the values of Vd of the drug, _Cmax and final T_1/2. The established clearance of itraconazole and its Vd depend on the patient’s body weight.

Indications

-Lesions of the skin and mucous membranes: vulvovaginal candidiasis; dermatomycosis; pityriasis; candidiasis of the oral mucosa; fungal keratitis.

– Onychomycosis caused by dermatophytes and / or yeast-like fungi.

– Systemic mycoses: systemic aspergillosis and candidiasis; cryptococcosis (including cryptococcal meningitis): in patients with immunodeficiency and in all patients with cryptococcosis of the central nervous system, itraconazole should be prescribed only in cases where 1st-line drugs are not applicable in this case or are ineffective; histoplasmosis; sporotrichosis; paracoccidioidomycosis; blastomycosis;other rarely occurring systemic or tropical mycoses.

Use during pregnancy and lactation

Pregnancy. Itraconazole should not be used during pregnancy, except in life-threatening cases, and if the expected positive effect for the mother exceeds the possible harm to the fetus. There are insufficient data on the use of itraconazole during pregnancy. In the post-marketing period, there were cases of congenital anomalies (visual, skeletal, genitourinary and cardiovascular disorders, chromosomal disorders, multiple malformations), but the causal relationship of these disorders with itraconazole intake was not reliably established. Data on the use of itraconazole in the first trimester of pregnancy did not reveal an increased risk of congenital anomalies. Women of childbearing age during treatment with itraconazole should use adequate methods of contraception throughout the course of treatment up to the onset of the first menstruation after its completion.

Breast-feeding. Itraconazole passes into breast milk. Breast-feeding should be discontinued during treatment.

Contraindications

-Hypersensitivity to itraconazole or excipients;

– Concomitant administration of CYP3A4 substrates (see section “Interaction with other medicinal products”), such as:

– levacetylmethadol, methadone;

– disopyramide, dofetilide, dronedarone, quinidine;

– telithromycin in patients with impaired renal function or liver disease, severe;

– ticagrelor;

– halofantrine;

– astemizole, mizolastine, terfenadine;

– ergot alkaloids: dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), eletriptan;

– irinotecan;

– lurasidone, midazolam for oral administration, pimozide, sertindole, triazolam;

– bepridil, the felodipine, lercanidipine, nicardipine;

– ivabradine, ranolazine;

– eplerenone;

– cisapride, domperidone;

– lovastatin, simvastatin, atorvastatin;

– fesoterodine in patients with insufficiency of the kidney or liver of moderate or severe degree, solifenacin in patients with insufficient renal function and severe deficiency of the liver of moderate or severe degree;

– colchicine in patients with disorders of the liver or kidneys.

– Chronic heart failure at present or in the anamnesis (except for the treatment of life-threatening or other dangerous infections, see the section “Special instructions”).

– Fructose intolerance, sucrose/isomaltase deficiency, glucose-galactose malabsorption.

– Children under 3 years of age.

– Pregnancy and breastfeeding.

With caution

With cirrhosis of the liver; severe liver and kidney function disorders; hypersensitivity to azoles; in elderly patients; in children.

Side effects

According to the World Health Organization (WHO), adverse events are classified according to their frequency as follows: very common (≥1/10), common (>1/100 and ><1/10), uncommon (>1/1000 and <1/10), uncommon (><1/100), rare (>1/10000 and <1/100), rare (><1/1000) and very rare (

Data from clinical trials

During 107 open-label and double-blind clinical trials involving 8,499 patients, where all patients took itraconazole at least once, the safety of treatment was evaluated.

Infectious and parasitic diseases: infrequently: rhinitis, sinusitis, upper respiratory tract infections.

Hematopoietic and lymphatic system disorders: rare: leukopenia; frequency unknown: neutropenia.

Immune system disorders: Infrequently: hypersensitivity.

Nervous system disorders: common: headache; rare: hypesthesia, paresthesia.

Hearing disorders and labyrinth disorders: rare: tinnitus.

Gastrointestinal disorders: common: abdominal pain, nausea; uncommon: dyspepsia, constipation, flatulence, diarrhea, vomiting; rare: dysgeusia.

Liver and biliary tract disorders: infrequently: hyperbilirubinemia, impaired liver function.

Skin and subcutaneous fat disorders: infrequent: rash, itching, hives.

Renal and urinary tract disorders: rare: pollakiuria.

Disorders of the reproductive system and mammary glands: infrequently: menstrual disorders; rarely: erectile dysfunction.

General complications and injection site reactions: rare: edematous syndrome.

The following is a list of adverse reactions associated with taking itraconazole in the form of an oral solution and/or an intravenous solution (with the exception of adverse reactions classified as “inflammation at the injection site”, since these adverse reactions are specific to the dosage form “solution for intravenous administration”).

Disorders of the hematopoietic and lymphatic systems: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

Metabolic disorders: hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia.

Mental disorders: confusion.

Nervous system disorders: peripheral neuropathy, dizziness, drowsiness.

Disorders of the cardiovascular system: heart failure, left ventricular failure, tachycardia, arterial hypertension, hypotension.

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

Disorders of the gastrointestinal tract: gastrointestinal disorders.

Liver and biliary tract disorders: hepatitis, jaundice, impaired liver function.

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary tract disorders: renal insufficiency, urinary incontinence.

General disorders and disorders at the injection site: generalized edema, facial edema, chest pain, hyperthermia, pain, fatigue, chills.

Influence on the results of laboratory parameters and instrumental studies: increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase, increased activity of alkaline phosphatase in blood plasma, increased activity of lactate dehydrogenase in blood plasma, increased concentration of blood urea, increased activity of gamma-glutamyltransferase, increased activity of liver enzymes, deviation from the norm of indicators of the general urinalysis.

Children. The safety of itraconazole was evaluated in 14 clinical trials (4 double-blind, placebo – controlled studies,9 open-label studies, and 1 open-label study followed by a double-blind study) involving 165 children aged 1 to 17 years. In the course of research, it was noted that the most common adverse reactions were: headache, vomiting, abdominal pain, diarrhea, impaired liver function, nausea, urticaria. The nature of adverse reactions that occur in children is similar to that observed in adult patients; however, the frequency of adverse reactions in children is higher.

Side effects reported in the post-marketing period (data obtained based on spontaneous reports)

The reported frequency of adverse reactions is based on clinical experience with the use of itraconazole in capsule form after registration.

Immune system disorders: very rare: serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.

Metabolic disorders: very rare: hypertriglyceridemia.

Nervous system disorders: very rare: tremor.

From the side of the organ of vision: very rare: blurred vision, diplopia.

Hearing disorders and labyrinth disorders: very rare: persistent or temporary hearing loss.

From the cardiovascular system: very rare: chronic heart failure.

Respiratory system disorders: common: shortness of breath.

From the gastrointestinal tract: very rare: pancreatitis.

From the side of the hepatobiliary system: very rare: severe toxic liver damage (including several cases of acute liver failure with a fatal outcome).

Skin and subcutaneous fat disorders: very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exentematous pustulosis, erythema polymorphic, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.

Influence on the results of laboratory parameters and instrumental studies: very rare: increased blood creatine phosphokinase activity.

Interaction

Itraconazole is primarily metabolized by the CYP3A4 isoenzyme. Other drugs that are also metabolized with the participation of this isoenzyme or change its activity may affect the pharmacokinetics of itraconazole. Similarly, itraconazole may affect the pharmacokinetics of drugs that are also metabolized with the participation of this isoenzyme. Itraconazole is a strong inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. When using itraconazole together with other medications, it is recommended to read the instructions for use to find out how the drug is metabolized and decide whether it is necessary to change its dose.

Medications that may reduce the concentration of itraconazole in blood plasma

Medications that reduce the acidity of gastric juice (for example, antacids, such as aluminum hydroxide, or agents that suppress the secretion of hydrochloric acid, such as H2-histamine receptor antagonists and proton pump inhibitors), disrupt the absorption of Itraconazole. These medications are recommended to be used with caution in combination with itraconazole:

– Itraconazole is recommended to be taken together with acidic drinks (such as non-diet cola) when using medicines that reduce the acidity of gastric juice together.

– It is recommended to take medications that neutralize hydrochloric acid (for example, aluminum hydroxide) at least 1 hour before or 2 hours after taking Itraconazole.

– When taking medications together, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Co-administration of itraconazole with strong inducers of the CYP3A4 isoenzyme may reduce the bioavailability of itraconazole and hydroxyitraconazole to such an extent that the effectiveness of the drug will decrease. Examples include the following drugs:

– Antibacterial agents: isoniazid, rifabutin, rifampicin.

– Anticonvulsants: carbamazepine, phenobarbital, phenytoin.

– Antiviral drugs: efavirenz, nevirapine.

Therefore, the use of strong inducers of the CYP3A4 isoenzyme together with itraconazole is not recommended. It is recommended to avoid prescribing these drugs for 2 weeks before starting itraconazole and during treatment with the drug, except in cases where the expected benefit exceeds the potential risk associated with a decrease in the effectiveness of itraconazole. When taking medications together, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Medications that may cause an increase in the concentration of itraconazole in blood plasma

Concomitant administration of itraconazole and strong inhibitors of the CYP3A4 isoenzyme may increase the bioavailability of itraconazole. Examples of strong inhibitors of the CYP3A4 isoenzyme:

– Antibacterial drugs: ciprofloxacin, clarithromycin, erythromycin.

– Antiviral agents: darunavir enhanced with ritonavir, fosamprenavir enhanced with ritonavir, indinavir, ritonavir and telaprevir.

These medications are recommended to be used with caution in combination with itraconazole. It is recommended to carefully monitor the condition of patients taking itraconazole together with strong inhibitors of the CYP3A4 isoenzyme, for timely detection of symptoms and signs of increased or prolonged pharmacological effects of itraconazole, if necessary, it is possible to reduce the dose of itraconazole. If possible, it is recommended to monitor the concentration of itraconazole in the blood plasma.

Medicinal products whose plasma concentrations may increase when co-administered with itraconazole

Itraconazole and its main metabolite hydroxyitraconazole can disrupt the metabolism of drugs metabolized by the CYP3A4 isoenzyme and interfere with the transport of drugs under the action of P-glycoprotein. This may lead to an increase in the plasma concentration of these drugs and / or their active metabolites when co-administered with itraconazole. An increase in the plasma concentration, in turn, can cause an increase or prolongation of both therapeutic and undesirable effects of these drugs, resulting in potentially life-threatening conditions. Thus, an increase in the concentration of certain drugs (terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindol, levomethadone) can lead to an increase in the QT interval and ventricular tachyarrhythmia, including cases of ventricular tachycardia of the “pirouette” type, which refers to potentially life-threatening conditions. After discontinuation of treatment, the plasma concentration of itraconazole decreases to an almost undetectable level within 7 to 14 days, depending on the dose of the drug and the duration of treatment. In patients with cirrhosis of the liver or those who simultaneously take inhibitors of the CYP3A4 enzyme, the decrease in the concentration of the drug may be even slower. This is especially important when starting therapy with medications whose metabolism is affected by itraconazole.

Interacting drugs are divided into the following categories::

– “Contraindicated”: Under no circumstances should this medicinal product be used in combination with itraconazole and for 2 weeks after discontinuation of itraconazole.

– “Not recommended”: It is recommended to avoid the use of this medicine during treatment and for 2 weeks after discontinuation of itraconazole, except in cases where the expected benefit exceeds the potential risk associated with the therapy. If the use of this combination of drugs cannot be avoided, it is recommended to monitor the patient’s condition for timely detection of symptoms and signs of increased or prolonged effects of drugs or the development of side effects, if necessary, treatment can be interrupted or the dose of drugs can be reduced. If possible, it is recommended to monitor the plasma concentration of drugs.

– “Use with caution”: careful monitoring should be carried out when using the drug together with itraconazole. When using medications together, it is recommended to monitor the patient’s condition for timely detection of symptoms and signs of increased or prolonged effects of drugs or the development of side effects, if necessary, treatment can be interrupted or the dose of medications can be reduced. If possible, it is recommended to monitor the plasma concentration of drugs.

The following are examples of drugs whose plasma concentrations may increase under the action of itraconazole. The drugs are divided into classes, and recommendations for joint use with itraconazole are also given. :

a See See also the section “Medications that may help reduce the plasma concentration of itraconazole”.

b See See also the section “Medicinal products that may contribute to an increase in the plasma concentration of itraconazole”.

Drugs whose plasma concentrations may decrease under the action of itraconazole

Concomitant administration of itraconazole with the nonsteroidal anti-inflammatory drug meloxicam may reduce the plasma concentration of meloxicam. It is recommended to prescribe meloxicam with caution simultaneously with itraconazole, as well as carefully monitor the patient’s clinical condition and the occurrence of side effects. If necessary, the dose of meloxicam should be adjusted.

Children

Drug interactions have only been studied in adults.

How to take, course of administration and dosage

For optimal absorption of the drug, Itraconazole should be taken immediately after meals. Capsules should be swallowed whole.

Elimination of Itraconazole from the skin and nail tissue is slower than from plasma. Thus, optimal clinical and mycological effects are achieved 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of treatment for nail infections.

* – the duration of treatment can be adjusted depending on the effectiveness of treatment.

Special patient groups

are children. Data on the use of Itraconazole for the treatment of children are limited. The use of Itraconazole for the treatment of children is not recommended, except in cases where the expected benefit of treatment outweighs the potential risk.

Elderly patients. Data on the use of Itraconazole for the treatment of elderly patients are limited. It is recommended to use Itraconazole for the treatment of patients in this category only if the expected benefit of treatment exceeds the potential risks. When choosing the dose of the drug for the treatment of elderly patients, it is recommended to take into account the decrease in liver, kidney and heart function, which is more common in the elderly, as well as the presence of concomitant diseases or taking other medications.

Liver function disorders. Data on the use of oral itraconazole for the treatment of patients with impaired liver function are limited. Caution should be exercised when prescribing the drug to this category of patients.

Impaired renal function. Data on the use of oral itraconazole for the treatment of patients with impaired renal function are limited. In some patients with renal insufficiency, itraconazole exposure may be reduced. Caution should be exercised when prescribing the drug to this category of patients. In some cases, it may be necessary to change the dose of the drug.

Overdose

The symptoms observed with an overdose of itraconazole were comparable to the dose-dependent adverse reactions observed with conventional doses of the drug.

Treatment: There is no specific antidote. In case of overdose, maintenance therapy should be carried out, gastric lavage should be performed with a solution of sodium bicarbonate, and activated charcoal should be given. Itraconazole is not removed from the body during hemodialysis.

Description

Solid gelatin capsules No.0 are opaque pink with a blue lid. The contents of the capsules are spherical microgranules (pellets) of white to cream color.

Special instructions

Effect on heart activity: in the study of itraconazole in the dosage form for intravenous administration, a transient, asymptomatic decrease in the left ventricular ejection fraction was noted, which normalized until the next infusion of the drug. The clinical significance of the data obtained for oral dosage forms is unknown.

Itraconazole has a negative inotropic effect. Cases of chronic heart failure associated with itraconazole have been reported. At a daily dose of 400 mg of itraconazole, a more frequent occurrence of heart failure was observed; at lower daily doses, this pattern was not detected. The risk of developing chronic heart failure is presumably proportional to the daily dose. The drug should not be used in patients with chronic heart failure or with a history of this symptom complex, except in cases where the possible benefit significantly outweighs the potential risk. Individual assessment of the benefit-risk ratio should take into account factors such as the severity of indications, dosage regimen, and individual risk factors for heart failure (coronary heart disease, valve damage, obstructive pulmonary disease, kidney failure, and other diseases accompanied by edema). Such patients should be informed about the signs and symptoms of chronic heart failure and monitored for their occurrence during the course of treatment. If such signs appear, the drug should be discontinued.

Life-threatening cardiac arrhythmias and / or sudden death have been reported in patients with concomitant use of methadone.

Drug interactions: concomitant administration of certain medications with itraconazole may result in changes in the efficacy of itraconazole and/or concomitantly administered medications, the occurrence of life-threatening adverse reactions, and/or sudden death. Medications that cannot be taken concomitantly with itraconazole, are not recommended for concomitant use, and/or are recommended for concomitant use with itraconazole with caution, are listed in the section “Interactions with other medications”.

Cross-hypersensitivity: data on the presence of cross-hypersensitivity between itraconazole and other antifungal agents with an azole structure (from the azole group) are limited. If hypersensitivity to other azoles is present, itraconazole should be used with caution.

Interchangeability: it is not recommended to use itraconazole interchangeably in the form of capsules and in the form of an oral solution, since the exposure of itraconazole is higher when used in the form of an oral solution than in the form of capsules, even when taking the same doses of itraconazole.

Reduced acidity of gastric juice: when the acidity of gastric juice is reduced, the absorption of itraconazole from capsules is disrupted. Patients with reduced gastric acid due to disease (for example, in patients with achlorhydria) or due to taking medications (for example, drugs that suppress gastric secretion), it is recommended to take itraconazole simultaneously with acidic drinks (such as non-dietary cola). The antifungal activity of the drug should be monitored and the dose of itraconazole should be increased if necessary.

Effects on liver function: in very rare cases, severe toxic liver damage has developed with the use of the drug, including several cases of acute liver failure with a fatal outcome. In most cases, this occurred in patients who already had liver diseases, in patients with other serious diseases, who were prescribed the drug for the treatment of systemic diseases, as well as in patients who received other drugs that have a hepatotoxic effect. However, some patients did not have comorbidities or obvious risk factors for liver damage. Some of these cases occurred in the first month of therapy, and some-in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy. If you experience symptoms that suggest the occurrence of hepatitis, such as anorexia, nausea, vomiting, weakness, abdominal pain and dark urine, you should immediately stop treatment and conduct a liver function study. Patients with increased activity of “liver” enzymes or liver disease in the active phase, or with a history of toxic liver damage due to taking other drugs, should not be prescribed treatment with itraconazole, except in cases where the expected benefit justifies the risk of liver damage. In such cases, it is necessary to monitor the activity of “liver” enzymes during treatment. Itraconazole is primarily metabolized in the liver. Since the total elimination half-life of itraconazole is slightly increased in patients with impaired liver function, it is recommended to monitor the plasma concentrations of itraconazole and adjust the dose of the drug if necessary.

Renal impairment: data on the use of the drug in patients with impaired renal function are limited, and in some patients with renal insufficiency, itraconazole exposure may be reduced. Therefore, such patients should be prescribed the drug with caution. It is recommended to monitor the concentrations of itraconazole in plasma and, if necessary, adjust the dose of the drug.

Immunodeficient patients: Oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as those with neutropenia, AIDS patients, or those undergoing organ transplantation.

Patients with life-threatening systemic fungal infections: due to the pharmacokinetic characteristics of itraconazole, its use is not recommended for starting treatment of life-threatening systemic mycoses.

AIDS patients: The attending physician should evaluate the need for maintenance therapy in AIDS patients who have previously received treatment for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and non-meningeal), and who are at risk of relapse.

Use in pediatric practice: since there are insufficient clinical data on the use of itraconazole in children, it is recommended to prescribe the drug to children only if the possible benefit of treatment outweighs the potential risk.

Women of childbearing age taking itraconazole should use adequate methods of contraception throughout the course of treatment until the onset of the first menstrual period after its completion.

Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Itraconazole.

In systemic candidiasis suspected to be caused by fluconazole-resistant Candida strains, sensitivity to itraconazole cannot be assumed, therefore, it is recommended to check sensitivity before starting itraconazole therapy.

Hearing loss: Temporary or permanent hearing loss has been reported in patients taking itraconazole. In some cases, hearing loss occurred while taking quinidine concomitantly (see sections “Contraindications” and “Interactions with other medications”). Hearing is usually restored after the end of Itraconazole therapy, but in some patients, hearing loss is irreversible.

Ability to conceive: animal studies have not shown the presence of reproductive toxicity in itraconazole.

Cystic fibrosis (cystic fibrosis): In patients with cystic fibrosis (cystic fibrosis), variability in the concentration of itraconazole in blood plasma was observed when using itraconazole in the form of an oral solution at a dose of 2.5 mg / kg 2 times a day. As a consequence, the therapeutic equilibrium concentration of itraconazole in the blood plasma may not be achieved. Steady-state concentrations > 250 ng / ml were achieved in approximately 50% of patients over 16 years of age and were not achieved in any patient under 16 years of age. If there is no response to Itraconazole therapy, consideration should be given to switching to alternative therapy.

Influence on the ability to drive vehicles and mechanisms

Studies on the effect of itraconazole on the ability to drive vehicles and work with machinery have not been conducted. It is necessary to take into account the possibility of adverse reactions, such as dizziness, visual impairment and hearing loss (see “Side effect”). If the described adverse events occur, you should refrain from performing these types of activities.

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Itraconazole

Conditions of release from pharmacies

By prescription

Dosage form

of capsule

Weight

Weight: 46 gr.