Orungal, oral solution 10mg/ml, 150ml

Composition

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1 ml. of the solution contains:

Active ingredient:

itraconazole 10 mg;

Auxiliary substances:

hydroxypropyl-β-cyclodextrin;

sorbitol 70% non-crystallizing solution;

sodium saccharinate;

propylene glycol;

concentrated hydrochloric acid;

sodium hydroxide;

flavorings (cherry, caramel);

purified water.

Pharmacological action

of ORUNGAL – antifungal.

Pharmacodynamics

Itraconazole inhibits the synthesis of ergosterol in the fungal cell membrane, which causes the antifungal effect of the drug.

Active against fungal infections:

• with dermatophytes (Trichophyton spp., Microsporum spp. Epidermophyton floccosum);
• yeast-like fungi and yeasts (Candida spp. including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp. Trichosporon spp. Geotrichum spp. );
• Aspergillus spp. ; Histoplasma spp. ; Responsible brasiliensis; Sporothrix schenckii; Fonsecaea spp. ; Cladosporium spp. ; Blastomyces dermatitidis; Pseudallescheria boydii; etc. Penicillium marneffei and

Candida glabrata and Candida tropicalis are the least sensitive to the action of Itraconazole by Candida species.

The main types of fungi that are not inhibited by itraconazole are Zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp. ), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

Pharmacokinetics

In general, itraconazole is well absorbed. Cmax in plasma is reached 2.5 hours after taking the drug. Itraconazole is metabolized in the liver with the formation of a large number of metabolites. The main metabolite is hydroxyitraconazole, whose plasma concentrations are almost 2 times higher than the corresponding concentrations of itraconazole. The final T 1/2 of itraconazole is 40 hours after repeated use. In patients with renal and hepatic insufficiency, the T1 / 2 of itraconazole is slightly increased.

The pharmacokinetics of itraconazole are characterized by non-linearity, as a result of which accumulation in plasma is achieved with prolonged use. Steady-state plasma concentrations of itraconazole are reached after 15 days with a Cmax of about 2 mcg / ml (when 200 mg of itraconazole is prescribed once a day). Clearance of itraconazole decreases at higher doses due to saturation of hepatic metabolism.

Itraconazole is rapidly absorbed after application of the solution. The absolute bioavailability of itraconazole when taking the drug with food is about 55%, when taking the solution on an empty stomach, the bioavailability of itraconazole increases by 30%.

Most of itraconazole in plasma binds to proteins (99.8%), mainly to albumin (for the metabolite of itraconazole — hydroxyitraconazole-the degree of protein binding is 99.6%). The affinity of itraconazole for lipids was also noted. Only 0.2% of itraconazole in plasma is presented in an unbound form.

Itraconazole penetrates well into tissues: concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles are 2-3 times higher than the corresponding plasma concentrations. The ratio of itraconazole concentrations in brain tissue and plasma is approximately the same.

The concentration of the drug in keratin tissues, especially in the skin, is approximately 4 times higher than the concentration in plasma.

The main metabolite is hydroxyitraconazole, which in vitro has an antifungal effect comparable to that of itraconazole.

The concentrations of the hydroxylated metabolite in plasma are almost 2 times higher than the corresponding concentrations of itraconazole.

As shown in in vitro studies, itraconazole is mainly metabolized with the participation of the enzyme CYP3A4.

About 35% of itraconazole in the form of inactive metabolites is excreted in the urine during the week and about 54% in the faeces. From 3 to 18% of the dose of the initial substance is excreted in the faeces. Renal excretion of the starting substance is less than 0.03% of the dose.

Indications

Treatment of oral and/or esophageal candidiasis in HIV-positive and immunodeficient patients; prevention of systemic fungal infections in patients with malignant blood diseases or in patients with bone marrow transplantation with a high probability of neutropenia (

Use during pregnancy and lactation

Pregnancy. Orungal® it should not be used during pregnancy except in life-threatening cases and if the expected positive effect exceeds the possible harm to the fetus.

Data on the use of Orungal®solution not enough during pregnancy. During the clinical use of the drug after registration, cases of congenital anomalies were noted. Such cases included visual, skeletal, genitourinary, and cardiovascular disorders, as well as chromosomal abnormalities and multiple malformations. However, whether the use of Orungal ® solution is the cause of these disorders has not been reliably established.

Epidemiological data on exposure to Orungal® in the first trimester of pregnancy, mainly in patients receiving short-term therapy for vulvovaginal candidiasis, did not reveal an increased risk of developing congenital anomalies compared to the control group, which was not exposed to any of the known teratogenic factors.

Women of childbearing age taking Orungal ® solution should use adequate methods of contraception throughout the entire course of treatment, up to the onset of the first menstruation after its completion.

Lactation. Since itraconazole can pass into breast milk, if it is necessary to use it during lactation, women using Orungal® should stop breastfeeding.

Contraindications

• concomitant use of drugs that metabolisierung with the participation of the enzyme CYP3A4 and can increase the QT interval, including terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levomethadone;
• concomitant use of midazolam for oral and triazolam;
• simultaneous reception of metabolisierung with the participation of the enzyme CYP3A4 inhibitors HMG-COA reductase inhibitors such as simvastatin and lovastatin;
• simultaneous use of ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine;
• hypersensitivity to Itraconazole and other components of the drug.

With caution:  the drug should be prescribed for cirrhosis of the liver, chronic renal failure, chronic heart failure, hypersensitivity to other drugs of the azole group, as well as for children and elderly patients.

Side effects

From the immune system:  very rarely — anaphylactic, anaphylactoid and allergic reactions.

Metabolic disorders:  very rarely — hypokalemia.

Nervous system disorders:  very rarely — peripheral neuropathy, headache, dizziness.

From the cardiovascular system:  very rarely — congestive heart failure.

Respiratory system disorders:  very rarely — pulmonary edema.

From the gastrointestinal tract:  very rarely — abdominal pain, vomiting, dyspepsia, nausea, loss of appetite, diarrhea, constipation.

From the side of the hepatobiliary system:  very rarely — severe toxic liver damage (including several cases of acute liver failure with fatal outcome), hepatitis, reversible increase in liver enzymes.

From the side of the skin and subcutaneous adipose tissue:  very rarely — Stevens-Johnson syndrome, angioedema, urticaria, alopecia, photosensitivity, rash, pruritus.

From the side of the reproductive system:  very rarely — violation of the menstrual cycle.

Common disorders:  very rarely — edematous syndrome.

Interaction

Medicinal products affecting the absorption of itraconazole

Drugs that reduce the acidity of gastric contents reduce the absorption of itraconazole, which is associated with the solubility of capsule shells.

Drugs that affect the metabolism of itraconazole

In studies, it was found that when Orungal interacts with rifampicin, rifabutin and phenytoin, the bioavailability of itraconazole and hydroxy-itraconazole is significantly reduced, which leads to a significant decrease in the effectiveness of the drug. Concomitant use of itraconazole with these drugs, which are potential inducers of liver enzymes, is not recommended. Interaction studies with other inducers of liver enzymes, such as carbamazepine, phenobarbital and isoniazid, have not been conducted, but similar results can be assumed. Since itraconazole is primarily metabolized by the CYP3A4 isoenzyme, potential inhibitors of this enzyme (ritonavir, indinavir, clarithromycin, and erythromycin) may increase the bioavailability of itraconazole.

Effect of itraconazole on the metabolism of other medicinesitraconazole can inhibit the metabolism of drugs metabolized by the CYP3A4 isoenzyme. This may result in an increase or prolongation of their effect (including side effects). Before starting to take concomitant medications, you should consult your doctor about the metabolic pathways of this drug, indicated in the instructions for medical use. After discontinuation of treatment, plasma concentrations of itraconazole decrease gradually depending on the dose and duration of treatment.This should be taken into account when evaluating the inhibitory effect of itraconazole on the metabolism of concomitantly administered drugs.

When conducting a course of treatment with Orungal, you can not prescribe: – terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindol, levomethadone, the use of which together with Orungal can lead to an increase in the concentration of these substances in 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 use and triazolam – HMG-CoA reductase inhibitors such as simvastatin and lovastatin metabolized by the CYP3A4 enzyme;-ergot alkaloid preparations such as dihydroergotamine, ergometrine, ergotamine and methylergometrine; – calcium channel blockers – in addition to the possible pharmacokinetic interaction associated with the common pathway of metabolism involving the CYP3A4 enzyme, calcium channel blockers have a negative effect on inotropic effect, which may enhance the similar effect of itraconazole.

When administered concomitantly with Orungal, plasma levels, effects, and side effects of oral anticoagulants should be monitored; HIV protease inhibitors (such as ritonavir, indinavir, and saquinavir); certain antitumor drugs (such as pink periwinkle alkaloids, busulfan, docetaxel, and trimetrexate); and calcium channel blockers metabolized by the CYP3A4 isoenzyme (dihydropyridine and verapamil); some immunosuppressive agents (such as cyclosporine, tacrolimus, sirolimus); some CYP3A4-metabolized HMG-CoA reductase inhibitors, such as atorvastatin; some CORTICOSTEROIDS, such as budesonide, dexamethasone, and methylprednisolone; and digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotisolam, midazolam (iv), rifabutin, methylprednisolone, Ebastine, reboxetine, repaglinide, disopyramide, cilostazol, eletriptan, halofantrin. When used concomitantly with Orungal, the dose of the above drugs should be reduced, if necessary.

There was no interaction between itraconazole and zidovudine and fluvastatin.

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

Effect on protein binding

In vitro studies have shown that there is no interaction due to competition for plasma protein binding between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, Indometacin, tolbutamide, and sulfamethazine.

How to take, course of use and dosage

Inside, on an empty stomach. The solution should be rinsed out of your mouth and then swallowed. After that, do not rinse your mouth with water.

Treatment of oral and/or esophageal candidiasis: 200 mg (2 scoops) per day in one or two doses for 1 week. If there is no positive effect after 1 week, treatment should be continued for another week.

Treatment of oral and/or esophageal candidiasis with resistance to fluconazole: 200-400 mg (2-4 scoops) per day in 1-2 divided doses for 2 weeks. If there is no positive effect after 2 weeks, treatment should be continued for another 2 weeks.

Prevention of fungal infections: 5 mg / kg / day in 2 divided doses. The drug is started one week before the start of cytostatic treatment or one week after the bone marrow transplant. Orungal® should be continued until the neutrophil count is restored (at least 1000 cells/µl).

Overdose

No overdose cases of Orungal have been reported.

Treatment: in case of accidental overdose, gastric lavage should be performed within the first hour after taking the drug and, if necessary, activated charcoal should be prescribed. Itraconazole is not eliminated by hemodialysis. There is no specific antidote.

Special instructions

Women of childbearing age taking Orungal® should use adequate methods of contraception throughout the course of treatment up to the onset of the first menstrual period after its completion.

In a study of the IV dosage form of Orungal® conducted on healthy volunteers, a transient, asymptomatic decrease in the left ventricular ejection fraction was noted, which normalized until the next infusion of the drug.

The clinical significance of the data obtained for oral dosage forms is unknown.

Itraconazole was found to have a negative inotropic effect. Caution should be exercised when taking itraconazole and BCC at the same time, which may have the same effect. Cases of congestive heart failure associated with Orungal®have been reported. Orungal® It should not be taken in patients with chronic heart failure or with a history of this disease, unless the possible benefit significantly outweighs the potential risk. Individual assessment of the benefit-risk ratio should take into account factors such as the severity of indications, dosage regimen, and individual risk factors for congestive heart failure. Risk factors include the presence of diseases such as coronary heart disease or heart valve damage; obstructive pulmonary disease; kidney failure or other diseases accompanied by edema. These patients should be informed about the signs and symptoms of congestive heart failure. Treatment should be carried out with caution, and the patient should be monitored for symptoms of congestive heart failure. If they occur, Orungal® should be discontinued.

With low stomach acidity: in this condition, absorption of itraconazole from Orungal®capsules violated. Patients taking antacid medications (such as aluminum hydroxide) are recommended to use them no earlier than 2 hours after taking Orungal ® capsules.

Patients with achlorhydria or using H2-histamine receptor blockers or proton pump inhibitors are recommended to take Orungal ® capsules with cola.

In very rare cases, when using Orungal® severe toxic liver damage developed, including cases of acute liver failure with a fatal outcome. In most cases, this was observed in patients who already had liver diseases, in patients with other serious diseases who received itraconazole therapy for systemic indications, as well as in patients who received other drugs that have a hepatotoxic effect. In some patients, no obvious risk factors for liver damage were identified. Some of these cases occurred in the first month of therapy, and some-in the first week of treatment.

In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy. Patients should be warned to contact their doctor immediately if they experience symptoms that suggest hepatitis, such as anorexia, nausea, vomiting, weakness, abdominal pain, and dark urine. If such symptoms occur, therapy should be stopped immediately and liver function tests should be performed.

Patients with elevated liver enzyme levels or active liver disease, or who have experienced toxic liver damage while taking other medications, should not be treated with Orungal® unless the expected benefit justifies the risk of liver damage. In these cases, it is necessary to monitor the level of liver enzymes during treatment.

Liver function disorders: itraconazole is primarily metabolized in the liver. Since the total T1/2 of itraconazole is slightly increased in patients with impaired liver function, it is recommended to monitor the plasma concentrations of itraconazole and adjust the dose of the drug if necessary.

Impaired renal function: Since the total T 1/2 of itraconazole is slightly increased in patients with renal insufficiency, it is recommended to monitor the plasma concentrations of itraconazole and, if necessary, adjust the dose of the drug.

Patients with immunodeficiency: The oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as those with neutropenia, AIDS patients, or those undergoing organ transplantation.

Patients with life-threatening systemic fungal infections: Due to its pharmacokinetic characteristics, Orungal® capsules are not recommended for starting treatment of life-threatening systemic mycoses.

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

Clinical data on the use of Orungal®capsules in pediatric practice, they are limited. Orungal®Capsules do not use in children unless the expected benefit outweighs the possible risk.

Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Orungal capsules.

There are no data on cross-hypersensitivity to itraconazole and other azole antifungal drugs.

Form of production

Solution for oral use

Storage conditions

At a temperature not exceeding 25 °C.

Shelf

life is 2 years.

Active ingredient

Itraconazole

Conditions of release from pharmacies

By prescription

Dosage form

solution for oral use

Purpose

Pregnant women as prescribed by a doctor, Children as prescribed by a doctor, Adults as prescribed by a doctor

Indications

Thrush, Fungus, Nail Fungus, Skin Fungus, Scalp Fungus