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

Hard gelatin capsules № 0, consisting of a transparent body of pink color and an opaque cap of blue color. The contents of capsules are pellets of cream color.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C.02 Itraconazole

Pharmacodynamics:

Orungal® is a synthetic broad-spectrum antifungal agent containing itraconazole, a triazole derivative. The mechanism of action of itraconazole is the inhibition of 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 the drug.

Itraconazole is active against infections caused by fungi:

dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum);
yeast-like mushrooms (Candida spp., Including C. albicans, C. iropicalis, 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 effects of itraconazole species Candida.

The main types of fungi, the development of which is not suppressed by itraconazole, are Zygomycetes (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 development of resistance include overexpression of the gene ERG11, which encodes the enzyme 14α-demethylase, which is the main target of azoles, and point mutations ERG11, leading to a decrease in the binding of enzymes to azoles and / or activation of transport systems, which leads to an increase in the 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_mOh) of itraconazole and AUC (the area under the curve "concentration-time") with multiple admission is 4-7 times higher than with a single admission. The maximum equilibrium concentration of itraconazole in plasma (C_ssmax) is about 2 μg / ml with the administration of 200 mg of itraconazole 1 time per day. The final half-life is usually 16-28 hours at a single admission and 34 - 42 hours with multiple admission. The concentration of itraconazole in the blood plasma is reduced to a practically undetectable value during 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 saturation of the ways of its metabolization in the liver.

Absorption

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

The absorption of itraconazole in capsules is reduced in patients with a decreased 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.The absorption of itraconazole fasting in such patients increases with Orungal®, capsules concomitantly with acidic beverages (such as nondietic cola). When taking Orungal®, capsules, at a dose of 200 mg once on an empty stomach together with a non-diet cola after a preliminary intake of antagonist H₂-gistaminovyh receptors ranitidine, itraconazole absorption was comparable to that of Orungal®, capsules, when only this preparation was taken.

Exposure of itraconazole is lower when taking itraconazole in the form of capsules compared to the exposure of itraconazole when taking the same dose as a solution for oral administration.

Distribution

Itraconazole binds 99.8% with 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> 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 plasma, while the concentration of the drug in tissues containing keratin, especially in the skin, is about 4 times higher than the concentration in the plasma.Concentration in the cerebrospinal fluid is much lower than in plasma, however, itraconazole has been shown to be effective against infectious agents present in the cerebrospinal fluid.

Metabolism

As shown in the studies in vitro, 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 concentrations of hydroxyitraconazole in plasma are about 2 times higher than the concentration of itraconazole.

Excretion

Itraconazole is excreted mainly in the form of inactive metabolites with urine (35%) and feces (54%) within one week after taking the solution for ingestion. Renal excretion of itraconazole and its active metabolite hydroxyitraconazole is less than 1% of the dose administered intravenously. Based on the results of the study of pharmacokinetics ¹⁴C-labeled drug after oral administration, excretion of unchanged itraconazole with feces 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 preserved for at least six months after the end of the 3-month course of treatment.

Special categories of patients

Impaired liver function

Itraconazole is predominantly metabolized 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, the average maximum concentration of itraconazole in plasma (C_mOh) was significantly lower (by 47%) than in healthy patients. The mean half-life of a single dose was increased in patients with cirrhosis and was 37±17 hours compared to 16±5 hours for healthy volunteers. The average exposure of itraconazole (area under the concentration-time curve - 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").

Impaired renal function

Data on the oral use of itraconazole 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 x 1.73 m², systemic exposure to itraconazole (AUC) was slightly 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 (T_mOh, FROM_mOh and AUC_0-8h).

After a single intravenous administration of the drug, the final half-life of itraconazole in patients with a small (defined in the study as creatinine clearance 50-79 ml / min), moderate (creatinine clearance 20-49 ml / min) or pronounced impaired renal function(creatinine clearance <20 ml / min) similar to that of healthy people (mean range 42-49 hours compared with 48 hours in patients with impaired renal function and healthy volunteers, respectively). The total exposure of itraconazole, based on the evaluation of the indicator AUC, was reduced in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, compared with patients in whom the kidney function is not impaired.

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

Children

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 performed using itraconazole in capsules, a solution for oral administration and a solution for intravenous administration. Individual doses of the preparation 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 the drug 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 AIT and itraconazole levels and its overall clearance; In rare cases, there was a slight correlation between the age of patients and the values of the volume of drug distribution, 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:

- Lesion of the skin and mucous membranes:

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

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

- 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 Orungal® should be prescribed only in cases where the first-line drugs are not applicable in this case or are ineffective;
histoplasmosis;
blastomycosis;
sporotrichosis;
paracoccidioidomycosis;
other seldom occurring systemic or tropical mycoses.

Contraindications:

- Hypersensitivity to itraconazole or excipients;

- aboutsimultaneous reception of preparations of isoenzyme substrates CYP3A4 (csection "Interaction with other medicines"), 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, methylergometrine (methylergonovine), eletriptan;
irinotecan;
lurasidone, 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 disease insufficiency at present or in the anamnesis (except for therapy of life-threatening or other dangerous infections.) See section "Special instructions");

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

- dUp to 3 years of age;

- bVariability and breastfeeding feeding.

Carefully:

- With cirrhosis of the liver;

- severe violations of liver and kidney function;

- hypersensitivity to other azoles;

- in elderly patients;

- in children (see also section "Special instructions").

Pregnancy and lactation:

Pregnancy

Orungal® should not be used during pregnancy, except in cases that threaten life, and if the expected positive effect for the mother exceeds the possible harm to the fetus.

In preclinical studies it was shown that itraconazole penetrates the placenta in rats.

Data on the use of Orungal® during pregnancy is not enough.During the clinical use of the drug after registration, cases of congenital anomalies were noted. Such cases included disorders of development of vision, skeleton, genitourinary and cardiovascular systems, as well as chromosomal abnormalities and multiple malformations. However, whether Orungal® is the cause of the occurrence of these disorders is not reliably established. Epidemiological data on the effect of Orungal® in the first trimester of pregnancy, mainly in patients receiving short-term therapy for vulvovaginal candidiasis, did not reveal an increased risk of congenital anomalies compared to a control group not exposed to any of the known teratogenic factors.

Women of childbearing age taking Orungal® should use adequate contraceptive methods throughout the course of treatment until the onset of the first menstrual period after completion.

Breast-feeding

Because the itraconazole can penetrate into breast milk, if it is necessary to use during breastfeeding, women who use Orungal® should stop breastfeeding.

Dosing and Administration:

For optimum absorption of the drug, Orungal® should be taken in capsules immediately after meals.

Capsules should be swallowed whole.

Indication				Dose				Duration of treatment
Vulvovaginal candidiasis			200 mg twice daily or 200 mg once a day					1 day or 3 days
Peregrine 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
Lesions of highly 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 Orungal® 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 Orungal®				2 nd year	Weeks free from taking the drug Orungal®				3rd year
Defeat nail records brushes	1st year	Weeks free from Orungal®				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

Excretion Orungal® of 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.

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 before 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 up to 1 year
Cryptococcal meningitis	200 mg twice daily	from 2 months up 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

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

Special patient groups

Children

Data on the use of Orungal®, capsules, for the treatment of children are limited. The use of Orungal®, capsules, for the treatment of children is not recommended, except when the expected benefit of the treatment exceeds the potential risk.

Elderly patients

Data on the use of Orungal®, capsules, for the treatment of elderly patients are limited. It is recommended that Orungal®, capsules, be used to treat patients in this category only if the expected benefit from treatment exceeds potential risks. 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 intake of other medicines.

Dysfunction of the liver

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

Renal impairment

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

Side effects:

Side effects of the drug are systematized relative to each of the organ systems depending on the frequency of occurrence, using the following classification:

Very often (≥1 / 10)

Often (≥1 / 100, <1/10)

Infrequently (≥1 / 1000, <1/100)

Rarely (≥1 / 10000, <1/1000)

Very rarely (<1/10000), including isolated cases

The frequency is unknown (can not be calculated from the available data).

Data from clinical trials

The safety of Orungal®, capsules, was studied in 107 open and double-blind clinical trials involving 8,499 patients. All 8,499 patients at least once took Orungal®, capsules, after which an evaluation of the safety of the treatment was conducted.

Infectious and parasitic diseases:

Infrequently: rhinitis, sinusitis, infections of the upper respiratory tract.

Disturbances from the hematopoietic and lymphatic systems:

Rarely: leukopenia;

Frequency unknown: neutropenia.

Immune system disorders:

Infrequent: 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: indigestion, 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:

Infrequent: rash, itching, hives.

Disorders from the kidneys and urinary tract:

Rarely: pollakiuria.

Disorders from the reproductive system and mammary glands:

Infrequent: violation of the menstrual cycle;

Rarely: erectile dysfunction.

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

Rarely: edematic syndrome.

Below is a list of unwanted reactions,associated with the use of itraconazole, which were recorded in clinical trials of Orungal® in the form of a solution for ingestion and / or in the form of a solution for intravenous administration (with the exception of adverse reactions referred to as "inflammation at the injection site", because these adverse 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 disorders.

Disorders 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.

Influence on the results of laboratory indicators and instrumental studies: increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase, increased activity of alkaline phosphatase in the 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 urinalysis.

Children

The safety of Orungal®, capsules,was evaluated in 14 clinical studies (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 postgistribution period (data obtained on the basis of spontaneous messages)

The presented incidence of adverse reactions is based on the clinical experience of using Orungal® after registration.

From the immune system:

Very rarely: serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.

Metabolic disorders:

Very rarely: hypertriglyceridemia.

Impaired nervous system:

Very rarely: tremor.

From the side of the organ of vision:

Very rarely: blurred vision, diplopia.

Hearing disorders and labyrinthine disturbances:

Very rarely: persistent or temporary hearing loss.

From the cardiovascular system:

Very rarely: chronic heart failure.

On the part of the respiratory system:

Often: shortness of breath.

From the gastrointestinal tract:

Very rarely: pancreatitis.

From the hepatobiliary system:

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

From the skin and subcutaneous fat:

Very rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustules, 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, observed with an overdose of Orungal®, capsules, 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, a gastric lavage with sodium bicarbonate solution should be made, Activated carbon. Itraconazole It is not removed from the body during hemodialysis.

Interaction:

Itraconazole is predominantly are metabolized isoenzyme FROMYRPA4. Other drugs that are also metabolized with the participation of this isoenzyme or alter its activity may affect the pharmacokinetics itraconazole. Similarly itraconazole can affect the pharmacokinetics drugs that are also metabolized with the participation of this isoenzyme. Itraconazole is a strong inhibitor of the isoenzyme CYP3A4 and P-glycoprotein. When itraconazole is used together with other drugs, it is recommended that you read the instructions for use to find out how the drug is metabolized and how to change the dose.

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

Drugs that reduce the acidity of gastric juice (for example, antacid agents such as aluminum hydroxide, or hydrochloric acid secretion inhibitors, such as H antagonists₂-gistaminovyh receptors and proton pump inhibitors), disrupt the absorption of Orungal®, capsules. These medications should be used with caution in combination with Orungal®, capsules:

- Itraconazole recommended 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 that medications, neutralizing hydrochloric acid (for example, aluminum hydroxide), at least 1 hour before or 2 hours after taking the Orungal® capsule.

- When sharing medicines, it is recommended that antifungal the 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 medicinal product.

Examples include the following drugs:

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.

Medications that can cause an increase in concentration itraconazole in blood plasma

Simultaneous reception of itraconazole and strong inhibitors of isoenzyme CYP3A4 can lead to an increased bioavailability of itraconazole. Examples of strong inhibitors of isoenzyme CYP3A4:

Antibacterials: ciprofloxacin, clarithromycin, erythromycin.
Antiviral drugs: darunavir strengthened with ritonavir, fosamprenavir, potentiated with ritonavir, indinavir, ritonavir and 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. If possible it is recommended to control the concentration of itraconazole in the blood plasma.

Medicines, whose concentrations in the blood plasma may increase when combined with itraconazole

Itraconazole and its main metabolite hydroxyitraconazole may break metabolism of drugs metabolized by isoenzyme CYP3A4 and prevent the transport 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 the data medicines, 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 and ventricular tachyarrhythmia, including cases of ventricular pirouette tachycardia, which is potentially life-threatening. After discontinuation of treatment, the plasma concentration of itraconazole decreases to almost indeterminate 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 enzyme inhibitors CYP3A4, the decrease in drug concentration 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.

Interacting medicines are divided into the following categories:

- "Contraindicated": Under no circumstances should this drug be used in combination with itraconazole and within two weeks after the discontinuation of itraconazole.

- "Not recommended": It is recommended to avoid the use of this medication during treatment and for two weeks after stopping itraconazole, unless the expected benefit exceeds the potential risk associated with the therapy. If you can not avoid using this combination of drugs, 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, le ix possible to interrupt or reduce the dose of drugs. If possible, it is recommended to control the plasma concentrations of drugs.

- "Use with caution": careful monitoring should be carried out when the medicinal product is combined with itraconazole.When using drugs together, it is recommended to monitor the patient's condition for the timely detection of symptoms and signs of increased or prolonged effects of drugs or the development of side effects, if necessary, treatment can interrupt or reduce the dose of medicines. 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. The drugs are divided into classes, and recommendations for joint use with itraconazole are also given:

Class medicinal means	Contraindicated	Not recommended	Use with caution
Alpha-blockers		Tamsulosin
Narcotic analgesics	Levacetyl metadol (levometadil), methadone	Fentanyl	Alfentanil, buprenorphine for intravenous and sublingual administration, oxycodone, sufentanil
Antiarrhythmics	Dizopyramide, dofetilide, dronedaron, quinidine		Digoxin
Antibacterial facilities	Telithromycin in patients with impaired renal or hepatic function	Rifabutin^a	Telithromycin
Anticoagulants and antiplatelet agents	Tikagrelor	Apixaban, rivaroxaban	Coumarins, cilostazol, dabigatran
Anticonvulsants		Carbamazepine^a
Antidiabetic drugs			Repaglinide saxagliptin
Anthelmintic and antiprotozoal agents	Halofantrine		Praziquantel
Antihistamines	Astemizole, misolastine terfenadine		Bilastin, ebastine
Medications against migraine	Ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), eletriptan
Antineoplastic agents	Irynotekan	Aksitinib, daphrafenib, dasatinib, Ibrutinib nilotinib, sunitinib trabetedin	Bortezomib buzulfan, docetaxel, erlotinib, gefitinib, imatinib, Ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids
Neuroleptics, anxiolytics 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, indinavir^b, ritonavir^b, saquinavir
Beta-blockers			Nadolol
Blockers "slow" calcium channels	Bepridil, felodipine, lercanidipine, nisoldipine		Other dihydropyridines, verapamil
Other drugs acting on the cardiovascular system	Ivabradin, ranolazine	Aliskiren, sildenafil in the treatment of pulmonary hypertension	Boszentan, riotsiguat
Diuretics	Eplerenone
Drugs affecting the organs of the gastrointestinal tract	Cisapride, domperidone		Aprepitant
Immunosuppressants		Everolimus	Budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus, tessirolimus
Drugs regulating lipid metabolism	Atorvastatin, lovastatin, simvastatin,
Drugs used to treat diseases of the respiratory system		Salmeterol
SSRIs, tricyclics and other antidepressants			Reboxetine
Preparations 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, oxybutynin, sildenafil in the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine
Other	Colchicine patients with impaired hepatic or renal function	Colchicine, conivaptan, tolvaptan	Alitretinoin (dosage forms for oral administration), zincalcet, mozavaptane

^a See also "Drugs that may help reduce the plasma concentration of itraconazole."

^b See also "Drugs that may increase the plasma concentration of itraconazole".

Preparaty, the plasma concentration of which can decrease under the action of itraconazole

Simultaneous application itraconazole with non-steroidal Panti-inflammatory the drug meloxicam may reduce the concentration of meloxicam in plasma. It is recommended that caution be given meloxicam simultaneously with itraconazole, and also carefully monitored clinical condition of the patient and occurrence of side effects. If necessary, the dose of meloxicam should be adjusted.

Children

Drug interactions are studied only in adults.

Special instructions:

- Influence on the activity of the heart: in the study of the drug form Orungal ® for intravenous administration there was a transient asymptomatic decrease in the left ventricular ejection fraction 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. There have been reports of cases of chronic heart failure associated with Orungal®. At a daily dose of 400 mg itraconazole, a more frequent occurrence of heart failure was observed; at lower daily doses, no such regularity was revealed. The risk of chronic heart failure presumably proportional to the daily dose. Orungal ® should not be taken in patients with chronic heart failure or with the presence of this symptom complex in the history, 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 monitor their appearance during the course of treatment. If these symptoms appear, the Orungal® should be discontinued.

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

- Drug Interactions: simultaneous administration of certain drugs with itraconazole may lead to a change in the efficacy of itraconazole and / or concomitant medications, the occurrence of life-threatening adverse reactions and / or sudden death. Drugs that can not be taken concomitantly with itraconazole,not recommended for simultaneous use and / or recommended for simultaneous use with itraconazole with caution, are listed in the 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. If there is hypersensitivity to other azoles, caution should be used itraconazole.

- Interchangeability: Orungal®, capsules, and Orungal®, oral solution, are not recommended because the exposure of itraconazole is higher when used in the form of a solution for ingestion than in the form of capsules, even when taking the same doses of itraconazole.

- Reduced acidity of gastric juice: with reduced acidity gastric absorption Itraconazole from the capsules is broken. Patients with reduced acidity of gastric juice due to disease (eg, patients with achlorhydria) or due to medication (eg, drugs,suppressing gastric secretion), it is recommended to take Orungal® in capsules concomitantly with acidic beverages (such as nondietic cola). It is necessary to monitor the antifungal activity of the drug and increase the dose of itraconazole if necessary.

- Effects on liver function: in very rare cases, using Orungal®, severe toxic liver damage developed, including several cases of acute hepatic insufficiency with a fatal outcome. In most cases, this was the case with patients who already had liver disease in patients with other serious illnesses that the drug was assigned to treat systemic diseases, as well as patients receiving other drugs with hepatotoxic effect. However, in some patients there were no concomitant diseases or obvious risk factors for liver damage. Several such 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 an increase in the activity of "liver" enzymes or liver disease in the active phase, or with transferred toxic liver damage due to the use of other drugs should not be prescribed treatment with Orungal ®, 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 plasma and, if necessary, adjust the dose of the drug.

- Renal impairment: data on the use of the drug in patients with impaired renal function is limited, in some patients with deficiency of kidney function exposure of itraconazole can be lowered.Therefore, such patients should be prescribed with caution. Recommended control of the concentrations of itraconazole in plasma and the need to adjust the dose of the drug.

- Patients with immunodeficiency: the bioavailability of itraconazole for oral administration may be reduced in some immunocompromised patients, for example, in patients with neutropenia who have AIDS or who underwent an organ transplant operation.

- Patients with systemic fungal infections that pose a life threat: Due to the pharmacokinetic characteristics of Orungal® in the form of capsules, its use is not recommended for the initiation of treatment of systemic mycoses that pose a threat to the lives of patients.

- AIDS patients: the attending physician should evaluate the need to prescribe supportive therapy for people with AIDS who have previously been treated for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and non-meninge) who are at risk of recurrence.

- Application in pediatric practice: Since clinical data on the use of Orungal® in children is not enough, it is recommended to prescribe the drug to children only if the possible benefit of the treatment exceeds the potential risk.

- Women of childbearing age, taking Orungal®, adequate contraceptive methods should be used throughout the course of treatment until the onset of the first menstrual period after completion.

- Treatment should be discontinued when peripheral neuropathy, which may be associated with the administration of Orungal® capsules.

- In systemic candidiasis, presumably caused by fluconazole-resistant strains Candida, we can not assume sensitivity to itraconazole, therefore, it is recommended to test the sensitivity before the initiation of itraconazole therapy.

- Hearing Loss: reported temporary or persistent hearing loss in patients taking itraconazole. In some cases, hearing loss occurred against a background of simultaneous administration with quinidine (see the sections "Contraindications" and "Interaction with other drugs").Hearing usually recovers after finishing therapy with Orungal®, but in some patients hearing loss is irreversible.

- Ability to conceive: Studies in animals have not shown the presence of reproductive toxicity in itraconazole.

- Cystic fibrosis (cystic fibrosis): in patients with cystic fibrosis (cystic fibrosis), the variability of the concentration of itraconazole in the blood plasma was observed with itraconazole in the form of a solution for oral administration 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 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 Orungal®, capsules should consider switching to alternative therapy.

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

Studies on the effect of the Orungal® drug on the ability to drive vehicles and work with machinery have not been conducted. It is necessary to take into account the possibility of occurrence of adverse reactions, such as dizziness, visual impairment and hearing loss (see "Side effect").When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Capsules 100 mg.

Packaging:

For 4, 5, 6 and 14 capsules in a blister of PVC and aluminum foil.

For 1 blister (4, 6 or 14 capsules) or 3 blisters (5 capsules each) or 2, 3 or 6 blisters (14 capsules) together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 15 to 30 ° 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:П N013888 / 01

Date of registration:17.04.2008 / 14.09.2016

Expiration Date:Unlimited

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Orungal® (Orungal®)