Itrazole - instructions for use, dose, side effects, contraindications

Itraconazole, pellets 464 mg :(active substance: itraconazole 100 mg; auxiliary matter: sugar pellets (sucrose 80.0-91.5%, corn starch 8,5-20,0%) 207.44 mg, poloxamer-188 (Loutrol) 25.94 mg, poloxamer-188 (Loutrol) micronized 0.51 mg, hypromellose 130.11 mg);

Hard gelatine capsules: titanium dioxide 2%, gelatin before 100%.

Description:

Hard gelatin capsules № 0 of white color.The contents of capsules are spherical microgranules from light yellow to brownish-yellow color.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C.02 Itraconazole

Pharmacodynamics:

Itraconazole is a synthetic broad-spectrum antifungal agent, a triazole derivative. Itraconazole inhibits the biosynthesis of ergosterol, the main component of the fungal cell membrane involved in maintaining the structural integrity of the membrane. Disruption of the synthesis of ergosterol leads to a change in membrane permeability and cell lysis, which determines the antifungal effect of itraconazole.

Itraconazole is active against infections caused by fungi:

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

- yeast-like mushrooms (Candida spp., Including C. albicans, S. tropicalis, C. parapsilosis, 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 many others.

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

The main types of fungi, the development of which is not suppressed by itraconazole, areZygomycetes (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 for the development of resistance include the overexpression of the ERG11 gene encoding the enzyme 14α-demethylase, which is the main target of the azoles, and the ERG11 point mutations, leading to a decrease in the binding of enzymes to the azoles and / or the activation of transport systems, leading to an increase in excretion of azoles . Cross-resistance was observed Candida spp. to preparations of the azole group, although resistance to one drug of this group does not necessarily mean the presence of resistance to other preparations of the azole group. Stresses have been reported Aspergillus fumigates, resistant to itraconazole.

Pharmacokinetics:

Due to nonlinear pharmacokinetics itraconazole accumulates in the blood plasma at multiple admission. The equilibrium concentration of itraconazole is usually achieved within about 15 days, while the maximum concentration (C_max) and itraconazole and the area under the "concentration-time" curve (AUC) with repeated admission is 4-7 times higher than with a single admission. The maximum equilibrium concentration of itraconazole in the blood plasma (C_ss_max) is about 2 μg / ml when applying 200 mg of itraconazole 1 time per day.The final half-life is usually 16-28 hours with a single dose and 34-42 hours with multiple administration. The concentration of itraconazole in the blood plasma is reduced to a practically undetectable value within 7-14 days after discontinuation of therapy, depending on the prescribed dose and duration of treatment. The clearance of itraconazole decreases at higher doses due to the saturation of its metabolism pathways in the liver.

Absorption

Itraconazole is rapidly absorbed after oral administration. The maximum concentration of unchanged itraconazole in the blood plasma is reached within 2-5 hours after ingestion. Absolute bioavailability of itraconazole after oral administration is about 55%. The maximum bioavailability of itraconazole is noted when taking capsules immediately after meals.

Suction

The absorption of itraconazole is reduced in patients with a low acidity of gastric juice, for example, when taking drugs that inhibit the secretion of hydrochloric acid in the stomach (such as antagonists of H₂-histamine receptors, proton pump inhibitors), or in patients with achlorhydria against a background of various diseases.Absorption of itraconazole fasting in such patients increases with simultaneous reception with acidic beverages (such as nondietic cola).

Distribution

Itraconazole binds 99.8% to blood plasma proteins, mainly with albumin (hydroxyitraconazole binds to albumin by 99.6%). Also affinity for lipids is noted. In unbound form, only 0.2% of itraconazole remains in the plasma. Apparent volume of distribution is more than 700 liters, which indicates its significant distribution in tissues. Concentrations in the lungs, kidneys, bones, stomach, spleen and muscles are 2-3 times higher than the corresponding concentrations in the blood plasma, while the concentration of the drug in tissues containing keratin, especially in the skin, is approximately 4 times higher than the concentration in the blood plasma . Concentration in cerebrospinal fluid is much lower than in plasma; nevertheless, the efficacy of itraconazole against the causative agents of infections present in the cerebrospinal fluid was demonstrated.

Metabolism

As shown in the studies in vitro, isoenzyme CYP3A4 is the main isoenzyme involved in the metabolism of itraconazole. Itraconazole is subject to active metabolism in the liver with the formation of a variety of metabolites. The main metabolite is hydroxyitraconazole, which in vitro has antifungal activity comparable to itraconazole. The concentration of hydroxyitraconazole in the blood plasma is approximately 2 times higher than the concentration of itraconazole.

BIntroduction

Itraconazole is excreted mainly in the form of inactive metabolites by the kidneys (35%) and through the intestine (54%). Based on the results of the study of pharmacokinetics ¹⁴C-labeled itraconazole after oral administration, the removal of unchanged itraconazole through the intestine varies from 3% to 18% of the dose.

Since the redistribution of itraconazole from tissues containing keratin is insignificant, the removal 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 stopping the 4-week treatment, and the concentration in the nail keratin, where itraconazole can be detected as early as 1 week after the start of treatment, is maintained for at least six months after the end of the 3-month course of treatment.

Pharmacokinetics in specific patient groups

Patients with impaired hepatic function

Itraconazole is metabolized predominantly in the liver. In the study of pharmacokinetics, the pharmacokinetic parameters of patients with cirrhosis of the liver and healthy volunteers were compared. In patients with cirrhosis of the liver with a single dose of 100 mg of itraconazole C_max was significantly lower (by 47%) than in healthy volunteers. The average half-life of a single dose was increased in patients with cirrhosis and was 37 ± 17 hours in this study compared to 16 ± 5 hours in healthy volunteers. Average AUC was similar in patients with cirrhosis of the liver and in healthy volunteers. Data on the long-term use of itraconazole in patients with cirrhosis of the liver are absent (see the sections "Dosing and Administration" and "Special instructions").

Patients with impaired renal function

Data on the use of itraconazole inward for the treatment of patients with impaired renal function are limited. In patients with uremia, in which the average creatinine clearance was 13 ml / min / 1.73 m², AUC was somewhat lower in comparison with the main population. There was no significant effect of hemodialysis or long-term peritoneal dialysis, conducted in outpatient settings, on the pharmacokinetics of itraconazole.

Data on prolonged use of itraconazole by patients with impaired renal function are limited. Dialysis does not affect the half-life or clearance of itraconazole or hydroxyitraconazole.

Patients of childhood

Data on the pharmacokinetics of itraconazole in pediatric patients are limited. Clinical studies of pharmacokinetics in children and adolescents aged 5 months to 17 years were carried out using itraconazole in the form of capsules, a solution for the duration of oral administration and a solution for intravenous administration. Individual doses of itraconazole in the form of capsules and oral solution varied from 1.5 to 12 5 mg / kg / day when taken once or twice a day. When taking itraconazole at the same daily dose twice a day compared with once a day, the maximum and minimum plasma concentrations were comparable to those in adult patients treated with itraconazole once a day. There were no significant age-related differences in indicators AUC itraconazole and its total clearance; In rare cases, there was an insignificant relationship between the age of patients and the volume distribution of itraconazole, C_max and a final half-life.The established clearance of itraconazole and its volume of distribution depend on the body weight of the patients.

Indications:

Fungal infections caused by itraconazole-sensitive pathogens:

- damage to the skin and mucous membranes:

vulvovaginal candidiasis;
colored lichen;
dermatomycosis;
Candidiasis of the oral mucosa;
fungal keratitis;

- onychomycosis caused by dermatophytes and / or yeast-like fungi;

- Systemic fungal infections:

systemic aspergillosis and candidiasis;
cryptococcosis (including cryptococcal meningitis): in patients with immunodeficiency and in all patients with cryptococcosis of the central nervous system itraconazole It should be used only if the first-line drugs are not applicable or ineffective;
histoplasmosis;
blastomycosis;
sporotrichosis;
paracoccidioidomycosis;
other seldom occurring systemic or tropical mycoses.

Contraindications:

- Dhypersensitivity to itraconazole or excipients;

- simultaneous reception of preparations of substrates isoenzyme CYP3A4 (see section "Interaction with other drugs"), such as:

levacetyl methadone, methadone;
disopyramide, dofetilide, dronedaron, quinidine;
Telithromycin in patients with impaired renal or hepatic function;
ticagrelor;
halofantrine;
astemizole, misolastine, terfenadine;
ergot alkaloids: dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergomethrin (methylergonovine), eletriptan;
irinotecan;
lourazidone, midazolam for oral administration, pimozide, sertindole, triazolam;
beprideil, felodipine, lercanidipine, nisoldipine;
ivabradine, ranolazine;
eplerenone;
cisapride, domperidone;
lovastatin, simvastatin, atorvastatin;
fesoterodine in patients with a moderate or severe degree of kidney or liver failure, solifenacin in patients with insufficient renal function of severe degree and with insufficient liver function of moderate or severe degree;
colchicine in patients with impaired hepatic or renal function;

- chronic heart failure at present or in the anamnesis (except for the therapy of life-threatening or other dangerous infections, see section "Special instructions");

- intolerance to fructose, sugarase / isomaltase deficiency, glucose-galactose malabsorption;

- children under 3 years;

- pregnancy and breastfeeding.

Carefully:

- Cliver irritation;

- severe violations of the liver and kidneys:

- increased sensitivity to other azoles;

- when used simultaneously with drugs that can increase or decrease the concentration of itraconazole in the blood plasma or with simultaneous use with drugs, the concentration of which in the blood plasma can change (see section "Interaction with other drugs");

- in elderly patients;

- in children older than 3 years (see also section "Special instructions").

Pregnancy and lactation:

Pregnancy

The drug Itrazol® is contraindicated in pregnancy.

Women of childbearing age taking the drug Itrazol®, it is necessary to use reliable contraceptive methods throughout the course of treatment until the onset of the first menstruation after its completion.

Breastfeeding period

Because the itraconazole can penetrate into breast milk; if necessary, breast-feeding should be discontinued.

Dosing and Administration:

Inside, right after eating.Capsules should be swallowed whole, washed down with a small amount of water.

The method of administration and dose of the preparation Itrazole® is given in Tables 1, 2.

Table 1

Indication				Dose				Duration of treatment
Vulvovaginal candidiasis			200 mg twice daily or 200 mg once daily					1 day or 3 days
Multicolored lichen			200 mg once a day					7 days
Dermatomycosis smooth skin			200 mg once a day or 100 mg once a day					7 days or 15 days
Defeats high-keratinized areas of the skin, such as hands and feet			200 mg 2 times a day or 100 mg once a day					7 days or 30 days
Candidiasis of the oral mucosa			100 mg once a day					15 days
Bioavailability of itraconazole for oral administration may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, AIDS patients or organ transplants. Therefore, a double dose increase may be required.
Fungal keratitis			200 mg once a day					21 day Duration of treatment can be adjusted depending on the improvement of the clinical picture
Onychomycosis caused by dermatophytes and / or yeast-like and mold fungi
Onychomycosis - pulse therapy	Doses and duration of treatment
	One course of pulse therapy is a daily intake of 2 capsules of the drug 2 times a day for 1 week. For treatment of fungal lesions of the nail plates of the brushes, 2 courses are recommended. For treatment of fungal lesions of the nail plates of the feet, 3 courses are recommended. The gap between the courses during which you do not need to take the drug is 3 weeks. Clinical results will become evident after the end of treatment, as the nails grow.
Localization onychomycosis	1st week	2 nd week		3rd week	4th week	5th week	6th week		7th week	8th week	9th week
Lesion of the nail plates of the toes with or without defeat of the nail plates of the fingers	1st year	Weeks free from taking the drug				2 nd year	Weeks free from taking the drug				3rd year
Defeat nail records brushes	1st year	Weeks free from taking the drug				2 nd year
Onychomycosis continuous treatment		Dose					Duration of treatment
Lesions of the nail plates of the feet with or without defeat of the nail plates of the brushes		200 mg per day					3 months

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

table 2

Systemic mycoses
Indication	Dose	Average duration of treatment *	Remarks
Aspergillosis	200 mg once a day	2-5 months	Increase the dose to 200 mg twice a day for invasive or disseminated disease
Candidiasis	100-200 mg once a day	from 3 weeks to 7 months	Increase the dose to 200 mg twice a day for invasive or disseminated disease
Cryptococcosis (except meningitis)	200 mg once a day	from 2 months to 1 year
Cryptococcal meningitis	200 mg twice daily	from 2 months to 1 year	Maintenance therapy, see section "Special instructions"
Histoplasmosis	from 200 mg once a day to 200 mg twice a day	8 months
Blastomycosis	from 100 m g once a day to 200 mg twice a day	6 months
Sporotrichosis	100 mg once a day	3 months
Paracoccidioidomycosis	100 mg once a day	6 months	Data on the effectiveness of this dose for the treatment of paracoccidioidomycosis in AIDS patients are absent
Chromomycosis	100-200 mg once a day	6 months

* Duration of treatment can be adjusted depending on the effectiveness of treatment.

Use in special patient groups

Patients of childhood

Data on the use of itraconazole in children is not enough. It is recommended to use the drug Itrazol® for the treatment of children over 3 years of age only if the possible benefit exceeds the potential risk.

Elderly patients

Data on the use of itraconazole for the treatment of elderly patients are limited. It is recommended to use the drug Itrazole^® for the treatment of this category of patients only if the expected benefit from the treatment exceeds the potential risk. When choosing a dose of the drug for the treatment of elderly patients, it is recommended to take into account the decrease in the function of the liver, kidney and heart, more common in old age, as well as the presence of concomitant diseases or the use of concomitant medications.

Patients with impaired hepatic function

Data on the use of itraconazole for the treatment of patients with impaired liver function are limited. Caution is necessary to prescribe a drug of this category of patients.

Patients with impaired renal function

Data on the use of itraconazole for the treatment of patients with impaired renal function are limited.In some patients suffering from renal insufficiency, exposure to itraconazole may be reduced. Caution is necessary to prescribe a drug of this category of patients. In some cases, a change in the dose of the drug may be required.

Side effects:

Classification of the incidence of adverse events according to the recommendations of the World Health Organization (WHO):

very often> 1/10;

often from> 1/100 to <1/10;

infrequently from> 1/1000 to <1/100;

rarely from> 1/10000 to <1/1000;

very rarely <1/10000, including individual messages;

the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Data from clinical trials

The safety of itraconazole in a capsule dosage form was studied in 107 open and double-blind clinical trials involving 8,499 patients. All 8,499 patients at least once took itraconazole in the dosage form of the capsule, followed by an evaluation of the safety of the treatment.

Infectious and parasitic diseases:

infrequently - rhinitis, sinusitis, infections of the upper respiratory tract.

Disturbances from the hematopoietic and lymphatic systems:

rarely - leukopenia;

frequency is unknown - neutropenia.

Immune system disorders:

infrequently - hypersensitivity.

Impaired nervous system:

often - headache;

rarely - hypoesthesia, paresthesia.

Hearing disorders and labyrinthine disturbances:

rarely - ringing in the ears.

Disorders from the gastrointestinal tract:

often - abdominal pain, nausea;

infrequently - dyspepsia, constipation, flatulence, diarrhea, vomiting;

rarely - dysgeusia.

Disorders from the liver and bile ducts:

infrequently, hyperbilirubinemia, impaired liver function.

Disturbances from the skin and subcutaneous fat:

infrequently - a rash, itching, hives.

Disorders from the kidneys and urinary tract:

rarely - pollakiuria.

Disorders from the reproductive system and mammary glands:

infrequent - menstrual cycle disorder;

rarely erectile dysfunction.

Complications of a general nature and reaction at the site of administration:

rarely - edematic syndrome.

Below is a list of undesirable reactions associated with the administration of itraconazole in the form of a solution for ingestion and / or in the form of a solution for intravenous administration, registered in clinical trials (with the exception of adverse reactions classified as "inflammation at the injection site",since these side reactions are specific for the dosage form "intravenous solution").

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

Immune system disorders: anaphylactoid reactions.

Disorders from the metabolism: hyperglycemia, hyperkalemia, hypokalemia. hypomagnesemia.

Disorders of the psyche: confusion of consciousness.

Impaired nervous system: peripheral neuropathy, dizziness, drowsiness.

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

Disturbances from the respiratory system, chest and mediastinal organs: pulmonary edema, dysphonia, cough.

Disorders from the gastrointestinal tract: gastrointestinal disorder.

Disturbances from the liver and bile ducts: hepatitis, jaundice, a violation of the liver.

Disturbances from the skin and subcutaneous tissues: erythematous rash, hyperhidrosis.

Disturbances from the musculoskeletal and connective tissue: myalgia, arthralgia.

Disorders from the kidneys and urinary tract: failure of kidney function, urinary incontinence.

General disorders and disorders at the site of administration: generalized edema, face swelling, chest pain, hyperthermia, pain, fatigue, chills.

Impact on laboratory results and instrumental research: increased alanine aminotransferase activity, increased activity of aspartate aminotransferase, increased activity of alkaline phosphatase in blood plasma, increased lactate dehydrogenase activity in blood plasma, increased blood urea concentration, increased activity of gamma-glutamyltransferase, increased activity of hepatic enzymes, deviation from the norm of general urine analysis.

Children

The safety of itraconazole in a capsule dosage form was evaluated in 14 clinical trials (4 double-blind, placebo-controlled studies, 9 open trials, and 1 study had an open phase followed by a double blind) involving 165 children aged 1 to 17 years.

During the 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 occurring in children is similar to that observed in adult patients; nevertheless, the frequency of adverse reactions in children is higher.

Side effects, registered in the post-registration period (data obtained on the basis of spontaneous messages)

The presented frequency of adverse reactions is based on the clinical experience of the use of itraconazole formulations after registration.

Immune system disorders:

very rarely - serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.

Metabolic disorders:

very rarely hypertriglyceridemia.

Impaired nervous system:

very rarely - a tremor.

Disorders from the side of the organ of vision:

very rarely - fuzzy vision, diplopia.

Hearing disorders and labyrinthine disturbances:

very rarely - persistent or temporary hearing loss.

Disorders from the cardiovascular system:

very rarely chronic heart failure.

Disturbances from the respiratory system, chest and mediastinal organs:

often - shortness of breath.

Disorders from the gastrointestinal tract:

very rarely - pancreatitis.

Disorders from the liver and bile ducts:

very rarely - severe toxic liver damage (including several cases of acute hepatic insufficiency with a fatal outcome).

Disturbances from the skin and subcutaneous tissues:

very rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, polymorphic erythema, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.

Influence on the results of laboratory indicators and instrumental studies:

very rarely - increased activity of creatine phosphokinase of blood.

Overdose:

Symptoms

Symptoms observed with an overdose of itraconazole were comparable to dose-related adverse reactions observed with conventional doses of the drug.

Treatment

There is no specific antidote. In case of overdosage, supportive therapy should be performed, during the first hour after taking the drug, rinsing the stomach with a solution of sodium bicarbonate. If necessary, the patient is assigned Activated carbon. Itraconazole It is not removed from the body during hemodialysis.

Interaction:

Itraconazole is mainly metabolized by isoenzyme CYP3A4. Other medications that are also metabolized with the participation of this proenzyme or alter its activity may affect the pharmacokinetics of itraconazole. Similarly itraconazole can affect the pharmacokinetics of drugs that are also metabolized with the participation of this proenzyme. Itraconazole refers to the strong inhibitors of the isoenzyme CYP3A4 and P-glycoprotein. When itraconazole is used together with other medications, it is recommended that you read the instructions for use to find out how the drug is metabolized and how to change its dose.

Medications that can help reduce the concentration of itraconazole in the blood plasma

Drugs that reduce gastric acidity (for example, antacid agents such as aluminum hydroxide, or hydrochloric acid secretion inhibitors, such as antagonists H₂-histamine receptors and proton pump inhibitors), interfere with the absorption of itraconazole. These medications should be used with caution in combination with the drug Itrazole^®. Itraconazole it is recommended to take together with acidic drinks (such as nondietic cola) with the joint use of drugs that reduce the acidity of gastric juice. It is recommended to take medicines that neutralize hydrochloric acid (for example, aluminum hydroxide), at least 1 hour before or 2 hours after taking the drug Itrazol®.

With the joint administration of medicines, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Combined use of itraconazole with strong isoenzyme inducers CYP3A4 can help reduce the bioavailability of itraconazole and hydroxyitraconazole to such an extent that the effectiveness of the drug will decrease.

Examples of strong isoenzyme inducers CYP3A4:

- antibacterial agents: isoniazid, rifabutin, rifampicin;

- anticonvulsants: carbamazepine, phenobarbital, phenytoin;

- antiviral drugs: efavirenz, nevirapine.

Thus, the use of strong isoenzyme inducers CYP3A4 together with itraconazole is not recommended. It is advisable to avoid prescribing these medicines for two weeks before starting itraconazole and during drug treatment, unless the expected benefit exceeds the potential risk associated with a decrease in the effectiveness of itraconazole. With the joint administration of medicines, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Drugs that can increase the concentration of itraconazole in the blood plasma

Simultaneous reception of itraconazole and strong inhibitors of isoenzyme CYP3A4 may increase the bioavailability of itraconazole.

Examples of strong inhibitors of isoenzyme CYP3A4:

- antibacterial preparations: ciprofloxacin, clarithromycin, erythromycin;

- antiviral agents: darunavir in combination with ritonavir; fosamprenavir in combination with ritonavir; indinavir, ritonavir, telaprevir.

These medications should be used with caution in conjunction with itraconazole. It is recommended that the condition of patients receiving itraconazole together with strong inhibitors of isoenzyme CYP3A4, for the timely detection of symptoms and signs of increased or prolonged pharmacological effects of itraconazole, if necessary, a reduction in the dose of itraconazole is possible.

Drugs, the concentration of which in the blood plasma may increase when combined with itraconazole

Itraconazole and its main metabolite hydroxyitraconazole may interfere with the metabolism of drugs metabolized by the isoenzyme CYP3A4, and to prevent transportation of drugs under the action of P-glycoprotein. This can lead to an increase in the plasma concentration of these drugs and / or their active metabolites when taken together with itraconazole. The increase in plasma concentration, in turn, can cause the enhancement or prolongation of both the 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, misolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levomethadone) may increase the interval QT on an electrocardiogram and ventricular tachyarrhythmia, including cases of ventricular pirouette tachycardia, which refers to potentially life-threatening conditions.

After discontinuation of treatment, the plasma concentration of itraconazole decreases to practically undetectable for 7 to 14 days, depending on the dose of the drug and the duration of treatment.

Life threatening cardiac arrhythmias and / or sudden death were noted in patients with simultaneous use of methadone.

In patients with cirrhosis of the liver or in patients simultaneously taking inhibitors of the isoenzyme CYP3A4, a decrease in the concentration of itraconazole may be even slower. This is especially important at the time of initiation of therapy with the use of drugs, the metabolism of which is affected itraconazole.

The nature of the interaction in the case of use in combination with itraconazole medications are divided into the following categories:

- "contraindicated"- under no circumstances should this drug be used in combination with itraconazole and within two weeks after stopping itraconazole;

- "Not recommended"- it is recommended to avoid the use of this medication at the time of treatment and within two weeks after discontinuing itraconazole, unless the expected benefit exceeds the potential risk associated with the therapy. If this combination of drugs can not be avoided, it is recommended to monitor the condition patient for the timely detection of symptoms and signs of increased or prolonged effects of drugs or the development of side effects, if necessary and treatment can interrupt or reduce the dose of drugs If possible it is recommended to control the plasma concentrations of drugs.;

- "apply with caution"- careful monitoring should be carried out when the drug is combined with itraconazole.With joint application it is recommended to monitor the patient's condition for the timely detection of symptoms and signs of increased or prolonged effects of the drugs or the development of side effects,if necessary, treatment can interrupt or reduce the dose of medications. If possible, it is recommended to monitor the plasma concentration of drugs.

Below are examples of drugs whose plasma concentration may increase under the action of itraconazole (Table 3). The drugs are divided into categories, and recommendations for joint use with itraconazole are also given.

Table 3

Pharmacotherapeutic Group	Categories of medicines by the nature of the interaction in case of use in combination with itraconazole
Pharmacotherapeutic Group	Contraindicated	Not recommended	Use with caution
Alpha-blockers	-	Tamsulosin	-
Analgesic drugs	Levacetylmethadol (levometadil) Methadone	Fentanyl	Alfentanil Buprenorphine for intravenous and sublingual administration Oxycodone Sufentanil
Antiarrhythmics	Disopyramide Dofetilide Dronedaron Quinidine	-	Digoxin
Anti-TB drugs	-	Rifabutin¹	Telithromycin
Anticoagulant and antiplatelet agents	Tikagrelor	Rivaroxaban Apixaban	Coumarins Cilostazolum Dabigatran
Antiepileptic facilities	-	Carbamazepine¹	-
Hypoglycemic agents for oral administration	-	-	Repaglinide Saxaglyptine
Anthelmintic and antiprotozoal agents	Halofantrine	-	Praziquantel
Antiallergic agents	Astemizole Misolastine Terfenadine	-	Ebastin Bilastin
Anti-migraine facilities	Ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergomethrin (methylergonovine) Eletriptan	-	-
Antineoplastic facilities	Irynotekan	Dasatinib Nilotinib Trabecectin Aksitinib Dafrafenib Ibrutinib Sunitinib	Bortezomib Buzulfan Docetaxel Erlotinib Ixabepilone Lapatinib Trimetrexate Vinca alkaloids
Antipsychotic drugs (antipsychotics), anxiolytic drugs (tranquilizers) and hypnotics	Lurasidone Midazolam for oral administration Pimozide Sertindole Triazolam	-	Alprazolam Aripiprazole Brotisolam Buspirone Haloperidol Midazolam for intravenous administration Perosporone Quetiapine Ramelteon Risperidone
Antiviral drugs	-	Symeprevir	Maraviroc Indinavir² Ritonavir² Saquinavir
Beta-blockers	-	-	Nadolol
blockers of "slow" calcium channels	beprideal felodipine lercanidipine nisoldipine	-	others dihydropyridines, including verapamil
renin inhibitors	-	aliskiren	-
antianginal agents	ivabradine ranolazine	sildenafil in the treatment of pulmonary hypertension	bosentan riotsiguat
diuretics	eplerenone	-	-
motor stimulants	cisapride	-	-
antiemetics	-	-	aprepitant domperidone
immunosuppressive agents	-	everolimus	budesonide ciclesonide ciclosporin dexamethasone fluticasone methylprednisolone rapamycin (sirolimus) tacrolimus tessirolimus
lipid-lowering drugs	atorvastatin lovastatin simvastatin	-	-
bronchodilating agents	-	salmeterol	-
antidepressants	-	-	reboxetine
drugs used in urology	Fesoterodine in patients with a moderate or severe degree of kidney or liver failure solifenacin in patients with insufficient renal function of severe degree and with insufficient liver function of moderate or severe degree	darifenacin vardenafil	fesoterodine imidafenacin oxybutin sildenafil in the treatment of erectile dysfunction solifenacin tadalafil tolterodine
m-holinoblokatory	-	-	tolterodine fesoterodine
others	colchicine (in patients with impaired liver or kidney function)	colchicine	alitretinoin (medicinal forms for oral administration) cinacalcet mozavaptane tolvoptan

¹ see also the section "Drugs that may help reduce the plasma concentration of itraconazole"

²see also the section "Drugs that may help increase the plasma concentration of itraconazole"

medicines, the plasma concentration of which can be reduced by the action of itraconazole

simultaneous application of itraconazole with a non-steroidal anti-inflammatory drug meloxicam can reduce the concentration of meloxicam in the blood plasma. it is recommended to carefully prescribe medications of meloxicam concomitantly with itraconazole, and carefully monitor the clinical state of the patient and the occurrence of side effects. if necessary, the dose of meloxicam should be adjusted.

patients of children's age

drug interactions have been studied only in adults.

Special instructions:

Influence on heart activity

Itraconazole has a negative inotropic effect. Cases of chronic heart failure associated with taking itraconazole have been reported. When taking 400 mg of itraconazole per day, a more frequent occurrence of heart failure was observed; at lower daily doses, no such regularity was revealed. The risk of chronic heart failure is presumably proportional to the daily dose. The drug Itrazol should not be taken in patients with chronic heart failure or with the presence of this symptom complex in an anamnesis, unless the possible benefit far exceeds the potential risk. Individual factors such as the severity of the indications, the dosing regimen, and individual risk factors for heart failure (coronary heart disease, valve lesions, obstructive pulmonary disease, renal failure, and other diseases accompanied by edema) should be taken into account when assessing the benefit-risk ratio individually. Such patients should be informed about the signs and symptoms of chronic heart failure and follow theirappearance during the course of treatment. If these symptoms appear, the use of Itrazole® should be discontinued.

Life threatening cardiac arrhythmias and / or sudden death were noted in patients with simultaneous use of itraconazole and methadone.

Drug Interactions

Simultaneous administration of certain drugs with itraconazole may lead to a change in the effectiveness of itraconazole and / or concomitantly used medications, to the occurrence of a dangerous lifetime of adverse reactions and / or sudden death (see section "Interaction with other drugs").

Cross-Hypersensitivity

Data on the presence of cross-over-hypersensitivity between itraconazole and other antifungal agents with an azole structure (from the azole group) are limited. In the presence of hypersensitivity to other azoles, caution should be used and itraconazole.

Reduced acidity of gastric juice

When reduced acidity of gastric juice, absorption of itraconazole is disrupted. Patients taking antacid preparations (eg, aluminum hydroxide),it is recommended to use them at least 1 hour before or 2 hours after taking the drug. Patients with achlorhydria or using blockers H₂-gistaminovyh receptors or proton pump inhibitors, it is recommended to take the drug Itrazol^® with drinks containing a non-diet coke. It is necessary to monitor the antifungal activity of the preparation Itrazole® and increase the dose as necessary.

Effects on liver function

AT very rare cases with the use of itraconazole developed severe toxic damage to the liver, including several cases of acute hepatic insufficiency with a fatal outcome. In most cases it has happened to patients who already had liver disease, patients with other serious diseases, which treatment was being administered to treat systemic diseases, and in patients treated with other drugs having hepatotoxic effect. However, in some patients there were no concomitant diseases 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. In case of symptoms suggestive of hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and darkening of urine, it is necessary to immediately stop treatment and conduct a study of liver function. Patients with increased activity of "hepatic" enzymes or liver disease in the active phase or with a transferred toxic liver damage due to the use of other drugs should not be prescribed treatment with the drug Itrazol^®, except when the expected benefit justifies the risk of liver damage. In such cases it is necessary during the treatment to monitor the activity of "liver" enzymes. Itraconazole mainly metabolized in the liver. Since in patients with impaired liver function the full half-life of itraconazole is slightly increased, it is recommended to monitor the concentrations of itraconazole in the blood plasma and, if necessary, adjust the dose of the drug.

Renal impairment

Data on the use of itraconazole in patients with impaired renal function are limited, in some patients with insufficient renal function, itraconazole exposure may be lowered. Therefore, such patients should be prescribed with caution. It is recommended to monitor the concentration of itraconazole in the blood plasma and, if necessary, adjust the dose of the drug.

Patients with immunodeficiency

The bioavailability of itraconazole for oral administration may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, HIV-infected patients or patients undergoing organ transplant surgery.

Patients with systemic fungal infections that are life threatening

It is not recommended for the beginning of treatment of systemic mycoses, which are a threat to the life of patients, to apply itraconazole in a dosage form for oral administration.

ATHIV-infected patients

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

Application in pediatric practice

Because clinical data on the use of itraconazole in children is not enough, it is recommended to prescribe the drug to children over 3 years only if the possible benefit of the treatment exceeds the potential risk.

Women of childbearing age, taking the drug Itrazol®, it is necessary to use adequate methods of contraception throughout the course of treatment until the onset of the first menstrual period after its completion.

Pperipheral neuropathy

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

Hearing Loss

A temporary or persistent hearing loss has been reported in patients taking itraconazole. In some cases, hearing loss occurred against a background of simultaneous administration with quinidine. Hearing usually recovers after the end of therapy with itraconazole, but in some patients hearing loss is irreversible.

In systemic candidiasis, presumably caused by fluconazole-resistant strains Candida, we can not assume sensitivity to infraconazole, therefore, it is recommended to check the sensitivity before starting therapy.

Ability to conceive

Studies in animals have not shown the presence of reproductive toxicity of itraconazole.

Cystic fibrosis (cystic fibrosis)

In patients with cystic fibrosis (cystic fibrosis), we observed a variability in the concentration of itraconazole in the blood plasma when itraconazole was administered in the form of an oral solution at dose 2.5 mg/kg 2 times a day. As a consequence, the therapeutic equilibrium concentration of itraconazole in the blood plasma can not be achieved. Equilibrium concentrations> 250 ng / mL were achieved in approximately 50% of patients over 16 years of age and were not achieved in any patient younger than 16 years. If there is no response to therapy with the drug Itrazole®, consider switching to alternative therapy.

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of itraconazole on the ability to drive vehicles and work with machinery were not conducted. It is necessary to take into account the possibility of adverse reactions such as dizziness, visual impairment and hearing loss.section "Side effect"). When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Capsules, 100 mg.

Packaging:

6 or 7 capsules in a contour cell box made of a polyvinylchloride film and aluminum foil.

One contour pack of 6 capsules, 2, 4, 6 or 12 contour packs of 7 capsules together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:P N003034 / 01

Date of registration:25.05.2009 / 30.07.2015

Expiration Date:Unlimited

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Laboratorios LICONSA, S.A. Spain

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp15.11.2017

Illustrated instructions

Instructions

Itrazole® (Itrazole®)