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

Excipients: hydroxypropyl betadex 400 mg, hydrochloric acid concentrated 3.76 μl, propylene glycol 100 μl, sodium hydroxide to pH 1.7-1.9, sodium saccharinate 0.6 mg, sorbitol solution 70% 190 μl, flavoring Cherry-1 0.25 mg, flavoring Cherry-2 0.5 mg, flavoring Caramel 0.2 mg, water purified to 1.0 ml.

Description:

Yellow or light orange solution with a cherry smell.

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. Itraconazole inhibits the synthesis of ergosterol cell membrane of fungi, which causes the antifungal effect of the drug. Itraconazole is active against infections caused by fungi:

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

- yeast-like mushrooms and yeast (Candida spp., including C. albicans, FROM. tropicalis, FROM. parapsilosis, FROM. 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 by many other.

Candida krusei, Candida glabrata and Candida tropicalis are the least sensitive to action itraconazole species Candida. The main types of fungi, development of which not suppressed itraconazole, are the 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:

Itraconazole is well absorbed when taken orally. Maximum plasma concentrations are achieved 2.5 hours after oral administration of the drug solution. 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, with the values of the maximum concentration (C_max) 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 with 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 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 saturation of the ways of its metabolization in the liver.

Absorption

Itraconazole is rapidly absorbed after oral administration. The maximum concentration in the plasma of itraconazole is reached within 2.5 hours after taking an empty stomach solution for ingestion. Absolute bioavailability of itraconazole when taking the drug with food is about 55%, with the administration of the solution on an empty stomach the bioavailability of itraconazole is increased by 30%.

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

Distribution

Most of itraconazole in the plasma binds to proteins (99.8%), mainly with albumin (for the metabolite itraconazole - hydroxyitraconazole - binding to proteins is 99.6%). The affinity of itraconazole for lipids is also noted.Only 0.2% of itraconazole in plasma is unbound. Itraconazole penetrates well into tissues: concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles are two to three times higher than the corresponding concentrations in blood plasma, while the concentration of the drug in tissues containing keratin, especially in the skin, is approximately 4 times 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

Itraconazole undergoes intensive metabolism in the liver with the formation of a large number of metabolites. As shown in the studies in vitro, itraconazole is metabolized mainly with the participation of isoenzyme CYP3A4. The main metabolite is hydroxyitraconazole, which in vitro has an antifungal action comparable to that of itraconazole. The concentrations of this metabolite in plasma are almost twice as high as the corresponding concentrations of itraconazole.

Excretion

About 35% of itraconazole in the form of inactive metabolites within a week is excreted in urine and about 54% - with feces. Renal excretion of the starting material and its active metabolite is less than 1% of the dose administered intravenously. From 3 to 18% of the dose of the original substance is excreted with feces.

Since the redistribution of itraconazole from keratin tissues is insignificant, the removal of itraconazole from these tissues is associated with the regeneration of the epidermis. Unlike blood plasma, the concentration in the skin persists for 2-4 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.

Special patient groups

Impaired liver function

Itraconazole is predominantly metabolized in the liver. According to a study of pharmacokinetics in patients with cirrhosis of the liver, a statistically significant decrease in the mean value of the C_mOh (47%) and twice the half-life (37 ± 17 hours compared to 16 ± 5 hours) of itraconazole compared to healthy people. Nevertheless, the overall systemic effect of itraconazole, (AUC) was the same in patients with cirrhosis of the liver and in healthy subjects. Data on the pharmacokinetics of itraconazole in patients with cirrhosis of the liver with long-term use of itraconazole are absent.

Impaired renal function

Data on the use of itraconazole for oral administration 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, calculated by AUC, was slightly lower than that of patients with normal renal function. There was no significant effect of hemodialysis or long-term peritoneal dialysis on the pharmacokinetics of itraconazole (T_mOh, FROM_max and AUC_0-8h).

After a single intravenous administration, the mean value of the final half-life of itraconazole in patients with impaired renal function is mild (creatinine clearance 50-79 ml / min), mean (creatinine clearance 20-49 ml / min) or severe (creatinine clearance <20 ml / min ) was similar to that of healthy volunteers (range of mean values of 42-49 hours compared with 48 hours in patients with impaired renal function and healthy volunteers, respectively).The systemic effect of itraconazole, calculated by AUC, was lower in patients with moderate and severe renal dysfunction of approximately 30% and 40%, respectively, compared with patients in whom renal function was not impaired.

There are no data on prolonged use of itraconazole by patients with impaired renal function. 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 a solution for oral administration 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 indicators AUC itraconazole and its total clearance, while in rare cases there was a slight correlation between the age of patients and the volume of distribution of the drug, 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.

Hydroxypropyl betadex

Bioavailability of hydroxypropyl betadeca used as a solvent for itraconazole in the oral solution is, on average, lower by 0.5% than when taking hydroxypropyl betadecks alone. Low bioavailability of hydroxypropyl betadex is not dependent on food intake and the frequency of administration.

Indications:

- Treatment of candidiasis of the oral cavity and / or esophagus in HIV-positive patients and patients with immunodeficiency;

- prevention of systemic fungal infections in patients with malignant blood diseases or in patients with bone marrow transplantation with a high probability of neutropenia (less than 500 cells / μl).

Contraindications:

- Hyperchuvstiteto itraconazole or excipients.

- Deficiency of sugar / isomaltase, intolerance to fructose, glucose-galactose malabsorption.

- Simultaneous reception of preparations of isoenzyme substrates CYP3A4 (see the 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, methylergometrine (methylergonovine), eletriptan;
irinotecan;
lurasidone, midazolam for oral administration, pimozide, sertindole, triazolam;
beprideil, felodipine, lercanidipine, nisoldipine;
ivabradine, ranolazine;
eplerenone;
cisapride, domperidone;
HMG-CoA reductase inhibitors, such as lovastatin, simvastatin, atorvastiMr.;
Fesoterodine in patients with a moderate or severe degree of kidney or liver failure, solifenacin In patients with a deficiency of renal function of severe severity and with Mr.insufficiency of liver function of moderate or severe degree;
colchicine in patients with impaired liver or kidney function.

- Clinically expressed ventricular dysfunction: congestive heart failure at present or in history (with the exception of therapy life-threatening or other dangerous infections. See section "Special instructions").

- Pregnancy, except for life-threatening events, and the period of breastfeeding (see the section on "Application during pregnancy and during breast-feeding").

Women of childbearing age who take Orungal® solution should use adequate methods of contraception throughout the course of treatment until the onset of the first menstrual period after it is completed.

Carefully:

- With hepatic insufficiency;

- with cirrhosis of the liver;

- with chronic renal failure;

- with acute heart failure;

- hypersensitivity to other azoles;

- in children and elderly patients (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 solution 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 the application of the Orungal solution 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 necessary during breastfeeding, women who use Orungal® should stop breastfeeding.

Dosing and Administration:

Inside. Take on an empty stomach, it is desirable to refuse to eat at least 1 hour after taking itraconazole. The solution should be rinsed for 20 seconds and then swallowed. After this, do not rinse your mouth with water.

Treatment of candidiasis of the oral cavity and / or esophagus

200 mg (2 measuring cups) per day in one or two doses for 1 week. In the absence of a positive effect after 1 week, treatment should continue for another week.

Treatment of candidiasis of the oral cavity and / or esophagus, with resistance to fluconazole

100-200 mg (1-2 measuring cups) 2 times a day for 2 weeks. In the absence of a positive effect after 2 weeks of treatment, the treatment is continued for another 2 weeks. In the absence of a positive effect, a daily dose of 400 mg can be taken no more than 14 days.

Prevention of fungal infections

Inside, 5 mg / kg of body weight per day in two divided doses. In clinical trials, preventive treatment was initiated immediately before treatment with cytostatics and usually one week before the transplant procedure.Orungal® is continued until the neutrophil count is restored (at least 1000 cells / μl).

Special patient groups

Children

Data on the use of the drug Orungal®, solution for oral administration, for the treatment of children are limited. The use of Orungal®, a solution, for the treatment of children is not recommended, except when the expected benefit exceeds the possible risk.

Prevention of fungal infections: there is no data on the effectiveness of the drug in children with neutropenia. Data on the safety of itraconazole, applied at a dose of 5 mg / kg body weight when taken 2 times a day, are limited.

Side effects such as diarrhea, abdominal pain, fever, vomiting, mucositis were more common in children than in adults. Nevertheless, the association of the occurrence of these adverse events with the administration of Orungal® has not been accurately established.

Elderly patients

Data on the use of Orungal®, a solution for the treatment of elderly patients, are limited. It is recommended that Orungal® be used to treat patients in this category only if the expected benefit from treatment exceeds potential risks.However, when choosing a dose of the drug for the treatment of elderly patients, it is recommended to take into account the decrease in liver, kidney and heart function, 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 itraconazole for oral administration in the treatment of patients with impaired liver function are limited. Caution is necessary to prescribe a drug of this category of patients.

Renal impairment

Data on the use of itraconazole for oral administration in 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:

Adverse reactions 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®, a solution for oral administration, was studied in clinical trials involving 889 patients participating in 6 double-blind and 4 open clinical trials. Each of the 889 patients at least once took Orungal®, an oral solution, after which an evaluation of the safety of the treatment was conducted.

Disturbances from the hematopoietic and lymphatic systems:

Infrequent: leukopenia, thrombocytopenia, neutropenia.

Immune system disorders:

Infrequent: hypersensitivity.

Disorders from the metabolism:

Infrequent: hypokalemia.

Impaired nervous system:

Often: headache, dizziness;

Infrequent: peripheral neuropathy, paresthesia, hyperesthesia;

The frequency is unknown: hypoesthesia.

Disturbances from the organ of hearing and balance:

Infrequent: ringing in the ears.

Disorders from the cardiovascular system:

Infrequent: heart failure.

Disturbances from respiratory system, chest and mediastinum:

Often: cough.

Disorders from the gastrointestinal tract:

Often: abdominal pain, vomiting, nausea, diarrhea, dysgeusia, indigestion;

Infrequent: constipation.

Disorders from the liver and bile ducts:

Infrequently: hyperbilirubinemia, impaired liver function.

Disturbances from the skin and subcutaneous fat:

Often: rash;

Infrequent: itching, hives.

Disturbances from the musculoskeletal system and connective tissue:

Infrequently: myalgia, arthralgia.

Violations from the organs of the reproductive system and mammary glands:

Infrequent: violation of the menstrual cycle.

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

Often: hyperthermia;

Infrequent: edematic syndrome.

Below is a list of unwanted reactions associated with taking itraconazole that were recorded in clinical trials of Orungal® in the form of capsules and / or in the form of a solution for intravenous administration (with the exception of adverse reactions classified as "inflammation at the injection site" because the data adverse reactions are specific for the dosage form "intravenous solution").

Infectious diseases: sinusitis, upper respiratory tract infections, rhinitis.

Disturbances from the hematopoietic and lymphatic systems: granulocytopenia.

Immune system disorders:anaphylactoid reactions.

Disorders from the metabolism: hyperglycemia, hyperkalemia, hypomagnesemia.

Disorders of the psyche: confusion of consciousness.

Disturbances from the nervous system: drowsiness.

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

Disturbances from the respiratory system. organs of the chest and mediastinum: pulmonary edema, dysphonia.

Disorders from the gastrointestinal tract: gastrointestinal disorders, flatulence.

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

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

Infringements from kidneys and urinary tract: a violation of kidney function, pollakiuria, urinary incontinence.

Violations from the organs of the reproductive system and mammary glands: erectile disfunction.

Complications of a general nature and reaction at the site of administration: generalized edema, face swelling, chest pain, pain, fatigue, chills.

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

Children

The safety of Orungal®, a solution for oral administration, was evaluated in five open clinical trials involving 250 children aged 6 months to 14 years.

During the research, it was noted that the most common adverse reactions were: vomiting, hyperthermia, diarrhea, mucositis, rash, abdominal pain, nausea, increased blood pressure, cough. The nature of adverse reactions occurring in children is similar to that observed in adult patients; nevertheless, the incidence of adverse reactions in children is higher.

Side effects registered in the postgistribution period¹

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 reactions.

Disorders from the metabolism:

Very rarely: hypertriglyceridemia.

Impaired nervous system:

Very rarely: tremor.

From the side of the organ of vision:

Very rarely: visual impairment, including blurred vision and diplopia.

From the side of the organ of hearing and balance:

Very rarely: persistent or temporary hearing loss.

From the cardiovascular system:

Very rarely: chronic cardiac failure.

From the respiratory system, chest and mediastinum:

Very rarely: dyspnea.

From the gastrointestinal tract:

Very rarely: pancreatitis.

From the liver and bile ducts:

Very rarely: severe toxic liver damage (including several cases acute hepatic insufficiency with a lethal 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 laboratory indicators:

Very rarely: increased activity of creatine phosphokinase

¹ data was obtained on the basis of spontaneous messages

Overdose:

Symptoms observed with an overdose of Orungal®, oral solution, 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 is metabolized by isoenzyme CYP3A4. Other medicines that also metabolized with the participation of this isoenzyme or change its activity, can affect the pharmacokinetics itraconazole. Similarly itraconazole can affect the pharmacokinetics drugs that are also metabolized with the participation of this isoenzyme, Itraconazole refers to strong inhibitors of isoenzyme CYP3A4 and P-glycoprotein. When using itraconazole together with other medications, it is recommended that you read the instructions for use to determine the metabolic pathway preparation and the decision of a question on necessity of change of its dose.

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

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 include the following drugs:

Antibacterial agents: isoniazid, rifabutin, rifamycin.
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 the use of itraconazole and during treatment with the drug, unless the expected benefit exceeds the potential risk associated with a decrease in the effectiveness of itraconazole. When taking drugs together, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug when occurrence of necessity.

Drugs that can cause an increase in the concentration of itraconazole in the 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, boosted with ritonavir, fosamprenavir, strengthened 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 effect of itraconazole, if necessary, it is possible to reduce the dose of itraconazole. If possible It is recommended that concentration of itraconazole in blood plasma.

Medicinale means, the concentration of which in the blood plasma may increase with simultaneous administration with itraconazole

Itraconazole and its main metabolite hydroxyitraconazole may interfere with the exchange of medications, 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. Increase in plasma concentration in the turn can cause the amplification or prolongation of both therapeutic and undesirable reactions of the data medicines.

Reception together with itraconazole medications metabolized by isoenzyme CYP3A4 and able to lengthen the interval QT on an electrocardiogram may be contraindicated, as this may lead to the development of ventricular tachyarrhythmias, including pirouette-type arrhythmia which is potentially life-threatening condition. After discontinuation of treatment, the plasma concentration of itraconazole decreases to almost indeterminate within 7-14 days, depending on the dose of the drug and the duration of treatment. In patients with cirrhosis of the liver or in patients concomitantly taking 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.

Table 1 presents examples of drugs whose concentration may increase under the action of itraconazole. The drugs are divided into classes, and recommendations for joint use with itraconazole are also given.

Interoperable medicinal preparations are divided into the following categories:

- "Contraindicated": not at which circumstances, this drug a drug at combination with itraconazole and within two weeks after termination of reception of itraconazole.

- "Not recommended": recommended avoid using this medication during treatment and for two weeks after stopping 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 patient's condition for the timely detection of symptoms and signs of intensification or prolongation or the development of side effects, if necessary, treatment can be interrupted or reduced by a dose of medications. If possible, it is recommended to monitor the plasma concentration 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.

Table 1.

Class of medicinal products	Contraindicated	Not are recommended	Use with caution
Alpha-adrenoblockers		Tamsulosin
Narcotic analgesics	Levacetyl metadol (levometadil), methadone	Fentanyl	Alfentanil, buprenorphine for intravenous and sublingual administration, oxycodone, sufentanil
Antiarrhythmic facilities	Dizopyramide, dofetilide, dronedaron, quinidine		Digoxin
Antibacterial facilities	Telithromycin in patients with impaired kidney or liver function severely	Rifabutin^a	Telithromycin
Anticoagulants and antiplatelet agents	Tikagrelor	Apixaban, rivaroxaban	Coumarins, cilostazol, dabigatran
Anticonvulsant drugs		Carbamazepine^a
Antidiabetic drugs			Repaglinide saxagliptin
Anthelmintic and antiprotozoal facilities	Halofantrine		Praziquantel
Antihistamines drugs	Astemizole, misolastine, terfenadine		Bilastin, ebastine
Medications against migraine	Alkaloids ergot, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), eletriptan
Countertumor drugs	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 drugs		Symeprevir	Maraviroc, indinavir^b, ritonavir^b, saquinavir
Beta-blockers			Nadolol
Blockers "slowMr.th " calcium channels	Bepridil, felodipine^c, lercanidipine, nisoldipine		Other dihydropyridines, verapamil
Other drugs, acting on the cardiovascular system	Ivabradin, ranolazine	Aliskiren, sildenafil in the treatment of pulmonary hypertension	Boszentan, riotsiguat
Diurethiki	Eplerenone
Preparations, 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
Preparations, plipolytic exchange regulation	Lovastatin, simvastatin, atorvastatin
Preparations, used to treat diseases of the respiratory system		Salmeterol
SSRIs, tricyclic and other antidepressants			Reboxetine
Preparations, used in urology	Fesoterodine in patients with deficiency of kidney or liver function of moderate or severe degree, solifenacin in patients with insufficient renal function of severe degree and with insufficient liver function of moderate or severe degree	Darifenacin, vardenafil	Fesoterodian, imidafenacin, oxybutynin, sildenafil in the treatment of erectile dysfunctionand, solifenacin, tadalafil, tolterodine
Other	Colchicine the 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".

^from Clinical studies have shown that with the simultaneous use of felodipine and itraconazole, an increase AUC itraconazole 6 times and C_m_Oh itraconazole 8 times.

Drugs whose plasma concentration may be reduced by itraconazole

Simultaneous use of itraconazole with non-steroidal anti-inflammatory

with meloxicam concentration meloxicam in plasma. It is recommended that caution be given meloxicam simultaneously with itraconazole, as well as carefully monitor the clinical condition of the patient and the 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 heart activity

In a study of the drug form of Orungal ® for intravenous administration, there was a transient asymptomatic decrease in the left ventricular ejection fraction, normalized to the next infusion of the drug. The clinical significance of the data obtained for oral dosage forms is unknown.

Itraconazole has a negative inotropic effect. Cases of acute heart failure associated with taking Orungal® were reported. At a daily dose of itraconazole 400 mg, a more frequent occurrence of heart failure was observed, at lower daily doses such a pattern was not revealed; the risk of acute heart failure is presumably proportional to the daily dose. Orungal® should not be taken to patients with acute heart failure or to the presence of this symptom complex in a history, unless the potential benefit far exceeds the potential risk.When evaluating the benefit-risk ratio individually, factors such as the severity of the indications, the dosage regimen, and individual risk factors for acute heart failure should be taken into account. Risk factors include the presence of cardiovascular diseases, such as ischemic heart disease or valve lesions; lung diseases such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the signs and symptoms of acute heart failure. Treatment should be conducted with caution, during treatment it is necessary to control the symptoms and signs of acute heart failure. If such signs or symptoms appear during the course of treatment, 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 result in a change in the efficacy of itraconazole and / orconcomitant medications used, 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 medicines".

Cross-Hypersensitivity

The data regarding the presence of cross-over hypersensitivity to itraconazole and other azoles are limited. If there is resistance to other azoles, caution should be used itraconazole.

Interchangeability

The use of Orungal®, capsule and Orungal®, an oral solution is 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 equal doses of itraconazole.

Cystic fibrosis (cystic fibrosis)

In patients with cystic fibrosis (cystic fibrosis) the variability of the concentration of itraconazole in blood plasma was observed with a constant intake of the solution at a dose of 2.5 mg / kg of body weight twice a day.As a consequence, the therapeutic equilibrium concentration of itraconazole in the blood plasma can not be achieved.

Application in pediatric practice

Since clinical data on the use of itraconazole in the form of a solution for oral administration for the treatment of children is not enough, it is recommended to administer itraconazole solution to children only if the possible benefit exceeds the potential risk. According to individual reports, itraconazole is used in pediatric practice for the prevention of fungal infections in patients with neutropenia at a dose of 5 mg / kg body weight when taken 2 times a day. Side effects such as diarrhea, abdominal pain, fever, vomiting, mucositis were observed more often than in adults. However, the association of the occurrence of these adverse events with the administration of Orungal® has not been accurately established.

Use in elderly patients

Since clinical data on the use of itraconazole solution for ingestion by elderly patients is not enough, it is recommended to administer itraconazole solution to such patients only if the possible benefit exceeds the potential risk.When choosing a dose of the drug for the treatment of this category of patients, it is recommended to take into account a decrease in the function of the liver, kidneys and heart, as well as the presence of concomitant diseases or the intake of other medications.

Effects on liver function

In very rare cases, with Orungal®, severe toxic liver damage developed, including 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 who received the drug for the treatment of systemic diseases with other serious illnesses, also in patients receiving other drugs that have a hepatotoxic effect. In some patients, there were no 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. Patients should be warned about the need to immediately contact their doctor in case of symptoms,suggesting the emergence of hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and darkening of urine. In the case of such symptoms it is necessary to immediately stop therapy and conduct a study of liver function.

Impaired liver function

Data on the use of itraconazole for oral administration to treat patients with impaired hepatic function are limited. The drug should be administered with caution in this category of patients. It is recommended to carefully monitor the condition of patients with impaired liver function in the treatment of itraconazole. When co-prescribing other drugs metabolized by the enzyme CYP3A4, it is recommended to take into account the fact that in the clinical study of a single oral intake of capsules of itraconazole with patients with cirrhosis, an increase in the half-life of the drug was observed. 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 concentration of itraconazole in the blood plasma and, if necessary, adjust the dose of the drug.

Impaired renal function

Since patients with renal insufficiency complete the half-life of itraconazole slightly increased, it is recommended to monitor the concentration of itraconazole in the blood plasma and, if necessary, adjust the dose of the drug.

Use in patients with severe neutropenia

Taking into account the pharmacokinetic properties of the Orungal® solution (see the section "Pharmacokinetics"), as well as the increased risk of rapid development of systemic candidiasis, patients with severe neutropenia should not use Orungal® solution as an initial therapy.

Cross-resistance

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.

Treatment should be discontinued when peripheral Neuropathy, which can be associated with the Orungal® solution.

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 (see Fig.sections "Contraindications" and "Interaction with other medicinal products"). Hearing usually recovers after finishing therapy with Orungal®, but in some patients, hearing loss was irreversible.

Ability to conceive

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

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 section "Side effect"). When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Solution for oral administration, 10 mg / ml.

Packaging:

For 150 ml of solution in a bottle of dark glass, with a screw-on lid with a mechanism to protect against accidental opening by children.

1 bottle complete with a measuring cup for 10 ml in a cardboard box together with instructions for use.

Storage conditions:

Store at a temperature not higher than 25 ° C, out of the reach of children.

Shelf life:

2 years.

After opening the package, the drug is usable for 1 month.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N011706 / 01

Date of registration:01.04.2011

Expiration Date:Unlimited

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

Manufacturer: & nbsp

JANSSEN PHARMACEUTICA, N.V. Belgium

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

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Orungal® (Orungal®)