Universal reference book for medicines
Product name: ORUNGAL ® (ORUNGAL ® )

Active substance: itraconazole

Type: Antifungal medication

Manufacturer: JOHNSON & JOHNSON (Russia) manufactured by JANSSEN PHARMACEUTICA (Belgium)
Composition, form of production and packaging
Solution for ingestion of
yellow or light orange color, with a cherry smell.

1 ml

itraconazole 10 mg

Auxiliary substances: hydroxypropyl betadec 400 mg, hydrochloric acid concentrated 3.76 mg, propylene glycol 100 μl, sodium hydroxide to pH 1.7-1.9, sodium saccharinate 0.6 mg, sorbitol 70% solution 190 μg, cherry flavor 1 0.25 mg, flavoring cherry 2 - 0.5 mg, caramel flavoring - 0.2 mg, purified water - up to 1 ml.

150 ml - bottles of dark glass (1) complete with a measuring cup for 10 ml - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

The description of the drug was approved by the manufacturer for the 2006 print edition.

PHARMACHOLOGIC EFFECT

Antifungal preparation of a wide spectrum of action, a derivative of triazole.
Inhibits the synthesis of ergosterol cell membrane of fungi, which causes the antifungal effect of the drug.
Itraconazole is active against infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum);
yeast-like and yeast fungi (Candida spp., including Candida albicans, Candida glabrata and Candida krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.);Aspergillus spp .; Histoplasma spp .; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp .; Cladosporium spp .; Blastomyces dermatitidis;Pseudoallescheria boydii; Penicillium marneffei and others.
Candida glabrata and Candida tropicalis are the least sensitive to the effects of itraconazole with Candida species.

The main types of fungi, the development of which is not inhibited by itraconazole, are Zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp., Absidia spp.), Fusarium spp., Scedosporium spp., Scopulariopsis spp.

PHARMACOKINETICS

Suction

After ingestion, it is well absorbed.
C max in plasma is observed after 2.5 hours. Absolute bioavailability of itraconazole with the intake of the drug with food is about 55%; when taken on an empty stomach bioavailability increases by 30%.
Distribution

Most of itraconazole in plasma binds to proteins (99.8%), mainly with albumin (for the metabolite itraconazole - hydroxy-itraconazole, the protein 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 2-3 times higher than the corresponding concentrations in the plasma.
The ratio of concentrations of itraconazole in brain tissues and plasma is approximately the same.
The concentration of the drug in keratin tissues, especially in the skin, is about 4 times higher than the concentration in the plasma.

With prolonged use of C ss itraconazole in plasma is achieved after 15 days.
With the administration of 200 mg of itraconazole 1 time / day on an empty stomach, C ssis about 2 μg / ml.
Metabolism

Itraconazole is biotransformed in the liver with the formation of a large number of metabolites.
One of the metabolites, hydroxy-itraconazole, has an antifungal activity in vitro, comparable to that of itraconazole. The concentration of hydroxy-itraconazole in the plasma is almost 2 times higher than the corresponding concentrations of itraconazole.
As shown in studies in vitro, itraconazole is metabolized mainly with the participation of the enzyme CYP3A4.

The clearance of itraconazole decreases at higher doses due to saturation of the hepatic metabolism.

Excretion

After repeated oral administration of itraconazole from the plasma is biphasic with a finite T 1/2 - 40 hours. From 3 to 18% of the administered dose is excreted with feces unchanged.
Unchanged in the urine output is less than 0.03%. About 35% of the dose is excreted as inactive metabolites with urine and about 54% with feces.
Pharmacokinetics in special clinical cases

T 1/2 of itraconazole in patients with renal and hepatic insufficiency is somewhat increased.

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).

DOSING MODE

In the treatment of candidiasis of the oral cavity and / or esophagus, Orungal is prescribed 200 mg (2 measuring cups) / day in 1 or 2 doses for 1 week.
In the absence of a positive effect after 1 week, the course of treatment should continue for another 1 week.
In the treatment of candidiasis of the oral cavity and / or esophagus, with resistance to fluconazole, 200-400 mg (2-4 measuring cups) / day in 1-2 divided doses for 2 weeks are prescribed.
In the absence of a positive effect after 2 weeks, treatment should continue for another 2 weeks.
For the prevention of systemic fungal infections, the drug is prescribed in a dose of 5 mg / kg body weight / day in 2 divided doses.
The drug is taken 1 week before the start of treatment with cytostatics or a week after the bone marrow transplantation and continues until the number of neutrophils is restored (at least 1000 cells / μl).
The solution should be taken orally, on an empty stomach.
The solution should be rinsed and then swallowed. After this, do not rinse your mouth with water.
SIDE EFFECT

All of the side effects listed below were encountered in some cases (less than 0.01%), including single cases.

On the part of the digestive system: dyspepsia, nausea, vomiting, diarrhea, abdominal pain, constipation, transient elevation of the level of hepatic enzymes in blood plasma, hepatitis.
In a few cases, severe toxic liver damage developed, including cases of acute hepatic insufficiency with a lethal outcome.
From the central nervous system and peripheral nervous system: headache, dizziness, peripheral neuropathy.

Allergic reactions: urticaria, angioedema, Stevens-Johnson syndrome, anaphylactic and anaphylactoid reactions.

Dermatological reactions: skin itching, rashes, photosensitivity, alopecia.

From the cardiovascular system: congestive heart failure, pulmonary edema.

On the part of the reproductive system: violations of the menstrual cycle.

Other: hypokalemia, edematous syndrome.

CONTRAINDICATIONS

- simultaneous reception of drugs metabolized with the participation of the isoenzyme CYP3A4 and capable of increasing the QT-interval, incl.
terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levomethadone;
- simultaneous administration of triazolam and oral midazolam;

- simultaneous administration of drugs metabolized with the participation of the CYP3A4 isoenzyme and HMG-CoA reductase inhibitors, such as simvastatin and lovastatin;

- simultaneous reception of ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine;

- Hypersensitivity to itraconazole and other components of the drug.

With caution should prescribe the drug for cirrhosis, chronic kidney failure, chronic heart failure, hypersensitivity to other drugs of the azole group, as well as children and elderly patients.

PREGNANCY AND LACTATION

Orungal should not be administered during pregnancy, except for life-threatening events and if the expected beneficial effect of therapy exceeds the possible risk to the fetus.

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 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 the control group not exposed to any of the known teratogenic factors.

Because itraconazole can be excreted in breast milk, if it is necessary to use Orungal during lactation, breastfeeding should be discontinued.

Women of childbearing age during the period of taking the drug should use adequate methods of contraception throughout the course of treatment until the onset of the first menstruation after it is completed.

APPLICATION FOR FUNCTIONS OF THE LIVER

With caution should prescribe the drug for chronic kidney failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution should prescribe the drug for cirrhosis.

APPLICATION FOR CHILDREN

Caution should be given to children.

APPLICATION IN ELDERLY PATIENTS

Caution should be given to elderly patients.

SPECIAL INSTRUCTIONS

In the study of intravenous drug Orungal, 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.
Cases of congestive heart failure associated with Orungal administration have been reported, and therefore the drug should not be taken to patients with congestive heart failure or the presence of this symptom complex in an anamnesis, unless the potential benefit far exceeds the potential risk. When assessing the benefit-risk ratio individually, the severity of the indications, the dosing regimen, and the risk factors for congestive heart failure should be taken into account. Risk factors include the presence of cardiovascular diseases, such as IHD or heart valve lesions; lung diseases such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Treatment Orungal in this case should be conducted with caution, while it is necessary to monitor the symptoms and signs of congestive heart failure. If such signs or symptoms appear during the course of treatment, Orungal should be discontinued.
In patients with cystic fibrosis, there was a change in the therapeutic levels of itraconazole with constant administration of the solution at a dose of 2.5 mg / kg body weight 2 times / day.

In very rare cases, with the use of Orungal, severe toxic liver damage developed (including cases of acute hepatic insufficiency with a fatal outcome).
In most cases, this occurred in patients with already existing liver diseases, or in patients to whom the drug was prescribed 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 Orungal therapy. Patients should be warned about the need for immediate medical attention in the event of symptoms suggesting the occurrence of hepatitis (anorexia, nausea, vomiting, weakness, abdominal pain and darkening of the urine). In the case of such symptoms it is necessary to immediately stop Orungal therapy and conduct a study of liver function. Patients with elevated levels of hepatic enzymes or liver disease in the active phase, or with transferred toxic liver damage due to taking other medications should not be prescribed Orungal, unless the expected benefit justifies the risk of liver damage. In these cases, it is necessary to control the level of hepatic enzymes during treatment.
When Orungal is appointed, patients with impaired hepatic and renal function due to the possibility of reducing the bioavailability of itraconazole are advised to monitor the concentrations of itraconazole in plasma and, if necessary, adjust the dose of the drug.

Taking into account the increased risk of rapid development of systemic candidiasis, patients with severe neutropenia should not use Orungal as a means of initial therapy.

In the case of neuropathy caused by Orungal solution, treatment should be discontinued.

Since clinical data on the use of Orungal in elderly patients is not enough, it is recommended to prescribe a solution of itraconazole to patients of this age group only if the potential benefit exceeds the possible risk.

Use in Pediatrics

Since clinical data on the use of Orungal solution in children is not enough, it is recommended to prescribe the drug to children only if the potential benefit exceeds the possible risk.

According to some reports, itraconazole is used in pediatric practice for the prevention of fungal infections in patients with neutropenia at a dose of 5 mg / kg of body weight when taken 2 times / day.
Side effects, such as diarrhea, abdominal pain, fever, vomiting, mucositis (inflammation of the oral mucosa), were more common in children than in adults. However, it is difficult to establish reliably what is the cause of these adverse reactions (Orungal or concomitantly taking chemotherapeutic drugs).
Impact on the ability to drive vehicles and manage mechanisms

Impact on the ability to drive and work with the technique Orungal does not have.

OVERDOSE

No cases of an overdose of Orungal were reported.

Treatment: with an accidental overdose within the first hour after taking the drug, gastric lavage is indicated.
If necessary, the patient is assigned activated charcoal.Itraconazole is not removed from the body by hemodialysis. There is no specific antidote.
DRUG INTERACTION

Medicines that affect the metabolism of itraconazole.

It has been established that inducers of microsomal oxidation in the liver (rifampicin, rifabutin and phenytoin) can reduce the bioavailability of itraconazole and, accordingly, reduce its effectiveness.

Studies on the interaction of itraconazole with other inducers of enzymes, such as carbamazepine, phenobarbital and isoniazid, have not been carried out, but a similar effect can be expected.

Because
itraconazole is mainly metabolized with the participation of the CYP3A4 isoenzyme, potential inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin can increase the bioavailability of itraconazole.
Effect of itraconazole on the metabolism of other drugs

Itraconazole can inhibit the metabolism of drugs metabolized by the CYP3A4 isoenzyme.
The result of this can be an increase or prolongation of their action (including side effects). After discontinuation of treatment, the concentrations of itraconazole in the plasma are reduced gradually depending on the dose and duration of treatment. This should be taken into account when assessing the inhibitory effect of itraconazole on the metabolism of concomitantly prescribed drugs.
When conducting a course of treatment Orungal can not be appointed :

-terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levomethadone, the use of which together with Orungal solution can lead to an increase in the concentration of these substances in the plasma, which in turn can cause an increase in the QT interval and, in rare cases, paroxysmal ventricular tachycardia of the "pirouette" type (torsade de pointes);

-midazolam for oral administration and triazolam;

- CYP3A4 enzyme-metabolized HMG-CoA reductase inhibitors, such as simvastatin and lovastatin;

- preparations of ergot alkaloids, such as dihydroergotamine, ergometrine, ergotamine and methylergometrine.

Care should be taken when taking Orungala and calcium channel blockers at the same time.
calcium channel blockers have a negative inotropic effect, which can enhance the similar effect of itraconazole. Itraconazole can reduce the metabolism of calcium channel blockers.
With a simultaneous appointment with Orungal should be monitored levels in the plasma, the effect, side effects of oral anticoagulants;
HIV protease inhibitors (such as ritonavir, indinavir, saquinavir); some antitumor drugs (such as vinca alkaloids pink, busulfan, docetaxel, trimetrexate); metabolized by the isoenzyme CYP3A4 calcium channel blockers (dihydropyridine and verapamil); some immunosuppressive agents (such as cyclosporine, tacrolimus, sirolimus); some metabolized isoenzyme CYP3A4 inhibitors of HMG-CoA reductase, such as atorvastatin; some GCS, such as budesonide, dexamethasone and methylprednisolone; as well as digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brothisolam, midazolam (w / w), rifabutin, methylprednisolone, ebastin, reboxetine, repaglinide, disopyramide, cilostazol, eletriptan, halofantrine. With a simultaneous application with Orungal dose of the above drugs, if necessary, should be reduced.
Interactions between itraconazole and zidovudine and fluvastatin were not detected.

There was no effect of itraconazole on the metabolism of ethinyl estradiol and norietetra.

Effect on binding to proteins

In vitro studies have demonstrated a lack of interaction due to competition for binding to plasma proteins, between itraconazole and such drugs as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethasine.

TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

List B. The drug should be stored out of reach of children at a temperature of no higher than 25 ° C.
Shelf life - 2 years. After opening the package, the drug is usable for 1 month.
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