Itrungar capsules 100 mg blister No. 15

Instructions for Itrungar capsules 100 mg blister No. 15

Composition

active ingredient: itraconazole;

1 capsule contains 100 mg of itraconazole;

excipients:

pellets contain: hydroxypropylmethylcellulose, corn starch, sucrose;

The capsule shell contains:

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

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

Dosage form

Capsules.

Main physicochemical properties: hard gelatin capsules with a yellow body and a green cap or vice versa (size 0); capsule contents are white to gray pellets.

Pharmacotherapeutic group

Antifungal drugs for systemic use. Triazole derivatives. ATX code J02A C02.

Pharmacological properties

Pharmacodynamics.

A triazole derivative, a synthetic antifungal agent, active against a wide range of pathogens. The mechanism of action is due to inhibition of the synthesis of ergosterol - an important component of the cell membrane of fungi. The following are sensitive to the drug: Trichophyton spp., Epidermophyton floccosum, Microsporum spp., Candida spp. (including C. albicans, C. glabrata and C. krusei), Cryptococcus neoformans, Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatidis and some other microorganisms. The clinical effect of the drug is fully manifested 2-4 weeks after the end of therapy in patients with skin mycoses and 6-9 months after the end of treatment in patients with onychomycosis (as the nails change).

Pharmacokinetics.

Absorption: the maximum bioavailability of itraconazole is observed when the drug is taken immediately after a meal. After a single dose of the drug, the maximum concentration of itraconazole in the blood plasma is observed after 2.5 hours. With prolonged use, a stable concentration of itraconazole in the blood plasma is achieved after 1-2 weeks and 3-4 hours after taking the last dose of the drug is: 0.4 μg/ml - when taking 0.1 g of the drug 1 time per day; 1.1 μg/ml - when taking 0.2 g of the drug 1 time per day, 2 μg/ml when taking 0.2 g of the drug 2 times per day.

Distribution: 99.8% of the active substance binds to blood plasma proteins. Itraconazole is distributed in various tissues of the body, with the concentration in the lungs, kidneys, liver, bones, stomach, spleen, skeletal muscles being 2-3 times higher than the concentration of itraconazole in blood plasma. The concentration of itraconazole in tissues containing keratin, especially in the skin, is 4 times higher than the concentration in blood plasma. The therapeutic concentration of itraconazole in the skin is maintained for 2-4 weeks after the end of a 4-week course of treatment. The therapeutic concentration of itraconazole in nail keratin is achieved 1 week after the start of treatment and is maintained for at least 6 months after the end of a 3-month course of treatment. Itraconazole also penetrates the sebaceous and sweat (to a lesser extent) glands of the skin.

Metabolism: Itraconazole is metabolized in the liver to form a large number of derivatives, one of which, hydroxyitraconazole, has antifungal activity comparable to itraconazole in vitro.

Elimination: Elimination of itraconazole from plasma is biphasic, with a terminal half-life of 1–1.5 days. Approximately 35% of the administered dose is excreted in the urine as metabolites within 1 week, of which less than 0.03% is excreted unchanged. Approximately 3–18% of the administered dose is excreted unchanged in the feces.

Pharmacokinetics in special clinical cases: in patients with renal and hepatic insufficiency, as well as in some patients with immunosuppression (e.g., in AIDS, neutropenia, after organ transplantation), the bioavailability of itraconazole may be reduced.

Indication

Mycoses caused by pathogens sensitive to itraconazole:

- vulvovaginal candidiasis;

- dermatological/ophthalmological fungal diseases: dermatomycosis, tinea versicolor; fungal keratitis;

- oral candidiasis;

- onychomycoses caused by dermatophytes, yeasts;

- systemic mycoses: systemic aspergillosis or candidiasis, cryptococcosis, including cryptococcal meningitis (the drug can be prescribed to immunocompromised patients with cryptococcosis and all patients with cryptococcosis of the central nervous system (CNS) only if treatment with other antifungal drugs is ineffective);

- histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other systemic mycoses, which occur extremely rarely.

Contraindication

Itrungar capsules are contraindicated in patients with known hypersensitivity to the drug or its components.

- CYP3A4 substrates that may prolong the QT interval, such as astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine. Concomitant use may result in increased plasma concentrations of these medicinal products, which may lead to increased or prolonged therapeutic and adverse reactions and potentially life-threatening conditions. For example, increased concentrations of these medicinal products may lead to QT prolongation and ventricular tachyarrhythmias, including ventricular fibrillation, a potentially fatal arrhythmia;

- HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as lovastatin and simvastatin;

- triazolam and oral midazolam;

- ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine);

- nisoldipine.

Itrungar 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").

Itrungar 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 the drug, 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 CYP3A4 activity 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. When used concomitantly with other drugs, the Summary of Product Characteristics of these drugs should also be consulted for information on the metabolic pathways and the possible need for dose adjustment.

Drugs that may reduce itraconazole plasma concentrations

Medicines that reduce stomach acidity (acid-neutralizing medicines such as aluminium hydroxide or acid-suppressing medicines such as H2-receptor antagonists and proton pump inhibitors) affect the absorption of itraconazole from the capsules. Caution should be exercised when using the following medicines and itraconazole capsules at the same time:

- when using itraconazole and acid-reducing drugs simultaneously, the drug should be used with drinks with increased acidity, such as non-diet cola;

- acid-neutralizing drugs (e.g. aluminum hydroxide) should be administered at least 1 hour before or 2 hours after administration of the drug;

- the level of antifungal activity should be monitored and, if necessary, the dose of itraconazole should be increased.

Concomitant use of itraconazole with potent CYP3A4 enzyme inducers results in a decrease in the bioavailability of itraconazole and hydroxyitraconazole, resulting in a significant reduction in the effectiveness of treatment. These drugs include:

- antibacterials: isoniazid, rifabutin (also see the subsection "Drugs whose plasma concentration is increased by itraconazole"), rifampicin;

- anticonvulsants: carbamazepine (also in the subsection "Medicines whose plasma concentration is increased by itraconazole"), phenobarbital, phenytoin;

- antivirals: efavirenz, nevirapine.

Concomitant use of potent CYP3A4 inducers with itraconazole is not recommended. The above-mentioned drugs should not be initiated 2 weeks before, during, or 2 weeks after treatment with itraconazole, unless the potential benefit clearly outweighs the potential risk. The level of antifungal activity should be carefully monitored and the dose of itraconazole increased if necessary.

Drugs that increase itraconazole plasma concentrations

Potent inhibitors of the CYP3A4 enzyme may increase the bioavailability of itraconazole. For example:

- antibacterial: ciprofloxacin, clarithromycin, erythromycin;

- antivirals: darunavir, ritonavir-boosted, fosamprenavir, ritonavir-boosted, indinavir, ritonavir (also in the subsection "Medicines whose plasma concentration is increased by itraconazole").

These drugs should be used with caution when used concomitantly with itraconazole. Such patients should be carefully monitored for symptoms of increased or prolonged pharmacological effects of itraconazole and, if necessary, the dose of itraconazole should be reduced. It is recommended to monitor the concentration of itraconazole in the blood plasma.

Itraconazole and its major metabolite hydroxyitraconazole may inhibit the metabolism of drugs metabolized by CYP3A4 and the transport of drugs by P-glycoprotein, which may lead to an increase in the concentration of these drugs and/or their metabolites in the blood plasma. Such an increase in plasma concentrations may lead to an increase or prolongation of the therapeutic effect and the occurrence of adverse reactions. The simultaneous administration of itraconazole and drugs metabolized by CYP3A4 and prolonging the QT interval is contraindicated, as this may lead to the occurrence of ventricular tachyarrhythmias, including cases of ventricular fibrillation with a fatal outcome. After discontinuation of treatment, the concentration of itraconazole decreases to a level that is almost undetectable in the blood plasma within 7 to 14 days, depending on the dose and duration of treatment. In patients with cirrhosis of the liver or in patients who are simultaneously using inhibitors of the CYP3A4 enzyme, the drug should be discontinued gradually. This is especially true for drugs whose metabolism is affected by itraconazole.

Concomitant medications are grouped into the following categories:

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 simultaneously and within 2 weeks after stopping itraconazole treatment should be avoided unless the benefit of treatment outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be carefully monitored for signs 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.

Use with caution: Close monitoring is recommended in case of concomitant use with itraconazole. Such patients should be carefully observed for symptoms of increased or prolonged pharmacological effect of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor the concentration of itraconazole in the blood plasma.

Examples of drugs whose concentrations increase when used concomitantly with itraconazole and recommendations for use

Table 1

Colchicine for patients

with impaired kidney and liver function

a See also “Drugs that decrease itraconazole plasma concentrations.”

b See also “Drugs that increase itraconazole plasma concentrations.”

Drugs whose concentration is reduced by itraconazole.

Concomitant use of itraconazole with meloxicam reduces the concentration of the latter. Meloxicam should be prescribed with caution when used concomitantly with itraconazole and therapeutic and side effects should be monitored. It is recommended to adjust the dose of meloxicam.

Children.

Drug interaction studies have only been conducted in adults.

Application features

Cross-hypersensitivity

There is no data on cross-sensitivity between itraconazole and other azole antifungals. Caution should be exercised when prescribing Itrungar capsules to patients with hypersensitivity to other azoles.

Effect on the heart

In studies with intravenous itraconazole in healthy volunteers, a transient, asymptomatic decrease in left ventricular ejection fraction was observed; it recovered before the next infusion. The clinical significance of these findings for oral formulations is unknown.

Itraconazole is known to have a negative inotropic effect, and cases of congestive heart failure have been reported in association with itraconazole. Among spontaneous reports, the incidence of congestive heart failure was higher with a total daily dose of 400 mg per day than with lower daily doses. Therefore, the risk of heart failure may increase with the total daily dose of itraconazole.

The drug should not be taken by patients with congestive heart failure or a history of it, except in cases where the expected benefit significantly outweighs the potential risk. When assessing the individual benefit/risk ratio, factors such as the severity of the diagnosis, dosage regimen and duration of treatment (total daily dose) and individual risk factors for the development of congestive heart failure should be taken into account. These risk factors include the presence of heart disease, such as ischemic heart disease or valvular disease; severe lung disease, including chronic obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the symptoms of congestive heart failure, treatment should be carried out with caution and symptoms of congestive heart failure should be monitored. If these symptoms appear during the course of treatment, the use of the drug Itrungar should be discontinued.

Calcium channel blockers may have a negative inotropic effect, which may potentiate the same effect of itraconazole. Itraconazole may also inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when itraconazole and calcium channel blockers are used simultaneously due to an increased risk of congestive heart failure (see section "Interaction with other medicinal products and other forms of interaction").

Effect on the liver

Severe hepatotoxicity, including cases of acute fatal hepatic failure, has been reported very rarely with itraconazole. Most of these cases occurred in patients with a history of liver disease who were being treated for systemic indications, had other serious illnesses and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases occurred during the first month of treatment, including the first week. Therefore, it is advisable to monitor liver function in patients taking Itrungar. Patients should be advised to seek immediate medical attention if symptoms of hepatitis occur, such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed.

Data on the use of oral forms of itraconazole in patients with hepatic impairment are limited. This drug should be used with caution in this category of patients. Close monitoring of patients with impaired hepatic function who are taking itraconazole is recommended. When deciding on treatment with other drugs that are metabolized by CYP3A4, it is recommended to take into account the prolonged half-life of itraconazole, which was observed in clinical studies in patients with cirrhosis who were given single doses of itraconazole capsules.

In patients with elevated liver enzymes, active liver disease, or hepatotoxicity from other medications, treatment should only be initiated if the expected benefit outweighs the risk of liver damage. In such cases, liver function should be monitored.

With reduced gastric acidity, the absorption of itraconazole from Itrungar capsules is impaired. Patients with reduced gastric acidity caused by disease (e.g. achlorhydria) or concomitant use of other drugs (e.g. to reduce acidity) are recommended to take the drug with drinks with increased acidity (e.g. non-diet cola) (see section "Interaction with other medicinal products and other types of interactions"). Antifungal activity should be monitored and the dose of itraconazole should be increased if necessary (see section "Interaction with other medicinal products and other types of interactions").

Elderly patients

Clinical data on the use of Itrungar capsules in elderly patients are limited. Itrungar capsules should not be used in elderly patients unless the benefit outweighs the potential risk.

Liver dysfunction

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when administering the drug to these patients.

Kidney dysfunction

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

Hearing loss

Cases of temporary or permanent hearing loss have been reported in patients taking itraconazole. In some cases, hearing loss occurred in the context of concomitant use with quinidine, which is contraindicated (see section 4.5). Hearing usually recovers after discontinuation of itraconazole therapy, but in some patients, hearing loss is irreversible.

Patients with immunodeficiency

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

Patients with life-threatening systemic fungal infections

Due to its pharmacokinetic properties (see section "Pharmacokinetics"), Itrungarne capsules are recommended for primary therapy of emergency conditions caused by systemic fungal infections.

Patients with AIDS

In patients with AIDS who have been treated for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are at risk of relapse, the physician should assess the need for maintenance therapy.

Neuropathy

If neuropathy occurs associated with the use of Itrungar capsules, treatment should be discontinued.

Carbohydrate metabolism disorders

This medicine contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

If, in the case of systemic candidiasis, it is suspected that the Candida species causing the disease are resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, a sensitivity test should be performed before starting treatment with Itrungar capsules.

Interaction potential

Concomitant use of itraconazole and certain medicinal products may alter the efficacy of itraconazole and/or the concomitant medicinal product, cause life-threatening adverse reactions and/or sudden death. Medicinal products that are contraindicated, should not be used or should be used with caution with itraconazole are listed in the section "Interaction with other medicinal products and other forms of interaction".

Use during pregnancy or breastfeeding

Pregnancy

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

In animal studies, itraconazole has shown reproductive toxicity.

Data on the use of itraconazole during pregnancy are limited. Cases of developmental anomalies, such as skeletal, genitourinary, cardiovascular and visual malformations, as well as chromosomal abnormalities and multiple malformations, have been reported. A causal relationship to itraconazole has not been established.

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

Women of reproductive age

Women of reproductive age taking Itrungar capsules should use reliable contraception throughout the entire course of treatment until the first menstruation after its completion.

Very small amounts of itraconazole pass into breast milk. Therefore, during breastfeeding, the possible risk to the child should be weighed against the expected benefit of treatment with Itrungar for the mother. In doubtful cases, the woman should stop breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect on the reaction rate when driving vehicles or operating other mechanisms have not been conducted. It should be borne in mind that side effects such as dizziness, visual disturbances and hearing loss may occur (see section "Adverse reactions"), which may lead to negative consequences when driving vehicles and operating other mechanisms.

Method of administration and doses

For optimal absorption of the drug, Itrungar capsules should be taken immediately after a high-calorie meal.

Capsules should be swallowed whole.

Table 2

Treatment of onychomycosis caused by dermatophytes and/or yeasts can also be carried out using pulse therapy (see table below).

Table 3

Optimal clinical and mycological effects are achieved 2–4 weeks after the end of treatment for skin infections, vulvovaginal candidiasis and oral candidiasis, and 6–9 months after the end of treatment for nail infections. This is due to the fact that the elimination of itraconazole from skin, nail and mucous membrane tissues is slower than from blood plasma.

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

Table 4

Elderly patients

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

Clinical data on the use of oral forms of itraconazole in patients with renal impairment are limited. Oral bioavailability of the drug may be reduced in patients with renal insufficiency. Caution should be exercised when using this drug in such patients and dose adjustment should be considered (see section 4.4).

Patients with liver dysfunction

Clinical data on the use of oral forms of itraconazole in patients with impaired liver function are limited. Caution should be exercised when using this medicinal product in such patients (see section 4.4).

Children

The use of the drug in children is not recommended.

Overdose

In general, the adverse reactions reported in case of overdose had a similar profile to the adverse reactions occurring with itraconazole (see section "Adverse reactions").

In case of overdose, supportive measures should be taken. Activated charcoal may be administered if appropriate. Itraconazole cannot be removed by hemodialysis. There is no specific antidote.

Adverse reactions

The most common adverse reactions with itraconazole reported in clinical trials and spontaneous reports were headache, abdominal pain and nausea. The most serious adverse reactions were serious allergic reactions, cardiac failure/congestive cardiac failure/pulmonary oedema, pancreatitis, severe hepatotoxicity (including several cases of acute hepatic failure with fatal outcome) and severe skin reactions. The frequency of adverse reactions and other adverse reactions are listed below.

The adverse reactions listed below were reported in open and double-blind clinical trials of itraconazole capsules involving 8499 patients receiving itraconazole for the treatment of dermatomycoses or onychomycoses, and from spontaneous reports.

The adverse reactions listed below are grouped by system organ class and within each system organ class, frequency is defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Infections and infestations:

infrequently - sinusitis, upper respiratory tract infections, rhinitis.

Blood and lymphatic system disorders:

rarely - leukopenia.

On the part of the immune system:

uncommon – hypersensitivity*;

rarely - serum sickness, angioedema, anaphylactic reactions.

Metabolism:

rarely - hypertriglyceridemia.

From the nervous system:

often - headache;

rarely - paresthesia, hypoesthesia, dysgeusia.

On the part of the organs of vision:

rarely - visual disturbances (including diplopia and blurred vision).

From the side of the organs of hearing and vestibular apparatus:

rarely - temporary or permanent hearing loss, tinnitus.

From the heart:

not known – congestive heart failure*.

On the part of the respiratory system:

rarely – dyspnea.

From the digestive system:

often - abdominal pain, nausea;

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

rarely - pancreatitis.

From the hepatobiliary system:

infrequently - liver dysfunction;

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

Skin and subcutaneous tissue disorders:

infrequently - urticaria, rash, itching;

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

From the urinary system:

rarely – pollakiuria.

From the reproductive system and mammary glands:

infrequently - menstrual disorders;

unknown - erectile dysfunction.

General disorders:

infrequently - edema.

Laboratory studies:

rarely –