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Active ingredients
Itraconazole
Release form
Capsules
Composition
1 capsule contains: Active substance: itraconazole (in the form of granules) 100 mg. Auxiliary substances: sucrose, hypromellose, macrogol. The composition of the shell of capsules: titanium dioxide, indigotin, azorubine, gelatin.
Pharmacological effect
Antifungal drug, a triazole derivative. Itraconazole is active against dermatophytes (Trichophyton, Microsporum, Epidermophyton floccosum); yeast and yeast-like fungi (Candida spp., including Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Pityrosporum spp., Trichsporon spp., Geotrichum spp.), Aspergillus spp., Histoplasma spp. spp., Cladosporium spp., Blastomyces dermatitidis, Pseudoallescheria boydii, Penicillium marneffei, as well as other yeast and mold fungi. Itraconazole disrupts the synthesis of ergosterol, an important component of the cell membrane of fungi, which causes the antifungal effect of the drug.
Pharmacokinetics
Absorption When ingested, the maximum bioavailability of itraconazole is observed when taking capsules immediately after a meal. Cmax in plasma is reached within 3-4 hours after ingestion. Distribution With prolonged use of Css itraconazole in plasma is reached within 1-2 weeks. Css 3-4 hours after taking the drug is 0.4 μg / ml (when taking the drug in a dose of 100 mg 1 time / day; 1.1 mcg / ml (when taken at a dose of 200 mg 1 time / day) and 2 mcg / ml (when taken at a dose of 200 mg 2 times / day). Binding to plasma proteins is 99.8%. The concentration of itraconazole in the blood is 60% of plasma concentrations. The accumulation of the drug in keratin tissues, especially in the skin, is about 4 times the accumulation in plasma, and its rate of excretion depends on the regeneration of the epidermis. In contrast to plasma concentrations that cannot be detected as early as 7 days after stopping therapy , therapeutic concentrations in the skin persist for 2-4 weeks Spruce after termination of a 4-week course of treatment. Itraconazole is detected in the keratin of the nails as early as 1 week after the start of treatment and persists for at least 6 months after the completion of the 3-month course of therapy. Itraconazole is also detected in sebum and to a lesser extent in sweat. Itraconazole is well distributed in tissues that are susceptible to fungal infections. Concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were 2-3 times higher than the corresponding concentrations in plasma. Therapeutic concentrations in the tissues of the vagina persist for 2 days after the end of the 3-day course of treatment at a dose of 200 mg / day,and 3 days after the end of a one-day course of treatment at a dose of 200 mg 2 times / day. Metabolism Itraconazole is metabolized in the liver to form a large number of metabolites, one of which, hydroxy-itraconazole, has an antifungal effect comparable to itraconazole in vitro. Antifungal concentrations of the drug, determined by the microbiological method, were about 3 times higher than those measured by HPLC. Excretion Excretion from plasma is two-phase, with a final T1 / 2 of 24-36 hours. Approximately 35% of the dose is excreted in the urine as metabolites within 1 week; unchanged with urine less than 0.03% is excreted. About 3–18% of the dose is excreted with feces. Pharmacokinetics in special clinical situations in patients with renal insufficiency and in patients with cirrhosis of the liver T1 / 2 itraconazole and its plasma concentration are slightly increased. The bioavailability of oral administration of itraconazole may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, AIDS patients, or in patients undergoing organ transplantation.
Indications
Treatment of mycoses caused by pathogens sensitive to the drug, including: - ringworm; - fungal keratitis; - onychomycosis, caused by dermatophytes and / or yeast and mold fungi; - systemic mycoses: systemic aspergillosis and candidiasis, cryptococcosis (including cryptococcal meningitis; in patients with immunodeficiency and in all patients with CNS cryptocosis, Orungal should be prescribed only in cases when first-line drugs are not applicable in this case or are ineffective), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blast ikoz and other systemic and tropical mycoses; - candidomycosis with damage to the skin and mucous membranes (including vulvovaginal candidiasis); - deep visceral candidiasis; - pityriasis versicolor.
Contraindications
- Simultaneous administration of drugs metabolized with the participation of the CYP3A4 enzyme and capable of increasing the QT interval, incl. - terfenadine, astemizole, mizolastine, cisapride, dofetilid, quinidine, pimozide, sertindol, levometadone; - Simultaneous intake of midazolam for ingestion and triazolam;such as simvastatin and lovastatin; - Simultaneous administration of ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine; - Increased sensitivity to itraconazole and other components of the drug. With caution, you should prescribe the drug for cirrhosis of the liver, chronic renal failure, chronic heart disease. to other drugs of the azoles group, as well as children and elderly patients.
Precautionary measures
Women of childbearing age who take oringal need to use adequate methods of contraception throughout the course of treatment until the onset of the first menstruation after its completion. Itraconazole has been found to have a negative inotropic effect. At the same time taking itraconazole and calcium channel blockers, which can have the same effect, care must be taken. Cases of congestive heart failure associated with taking an oringla have been reported. Orungal should not be taken in patients with chronic heart failure, unless the potential benefits far outweigh the potential risk.
Use during pregnancy and lactation
Orungal should be prescribed during pregnancy only when there is a life-threatening systemic mycosis, when the expected benefit to the woman exceeds the potential risk to the fetus. Since itraconazole is excreted in breast milk, if necessary, breastfeeding should be used during lactation. Women of childbearing age should be given use adequate methods of contraception throughout the course of treatment until the first menstruation after its completion.
Dosage and administration
Capsules should be taken immediately after a meal, swallowed whole. The oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as patients with neutropenia, AIDS patients or transplanted organs. Consequently, it may be necessary to double the dose. One course of pulse therapy consists in taking 2 capsules daily.Orungala 2 times / day (200 mg 2 times / day) for 1 week. For the treatment of fungal infections of the nail plate brushes, 2 courses are recommended. For the treatment of fungal infections of the nail plate foot, 3 courses are recommended. The interval between courses, during which you do not need to take the drug, is 3 weeks. Clinical results will become apparent after the end of treatment, as the nail grows. In addition to pulse therapy, it is possible to conduct a continuous course. The drug is prescribed in 2 capsules / day (200 mg 1 time / day) for 3 months. The withdrawal of Orungal from the skin and nail tissue is slower than from plasma. Thus, optimal clinical and mycological effects are achieved 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of the treatment of nail infections.
Side effects
On the part of the digestive system: dyspepsia (nausea, vomiting, constipation, diarrhea, loss of appetite), abdominal pain, a transient increase in the level of liver enzymes in the blood plasma, hepatitis. In very rare cases, severe toxic liver damage developed (including cases of acute liver failure with a fatal outcome). For the CNS and peripheral nervous system: headache, dizziness, peripheral neuropathy. Allergic reactions: in some cases - itchy skin, rash, urticaria, angioedema, Stevens-Johnson syndrome, anaphylactic and anaphylactoid reactions. Dermatological reactions: in some cases - alopecia, photosensitivity. From the cardiovascular system: edema and, congestive heart failure and pulmonary edema. Other: menstrual disorders, hypokalemia.
Overdose
Cases of drug overdose Orungal were not reported. Treatment: in case of accidental overdose during the first hour after taking the drug, gastric lavage should be carried out and, if necessary, activated charcoal should be administered. Itraconazole is not excreted by hemodialysis. There is no specific antidote.
Interaction with other drugs
Drugs that affect the absorption of itraconazole Drugs that reduce the acidity of gastric contents, reduce the absorption of itraconazole,which is related to the solubility of capsule shells. Drugs affecting the metabolism of itraconazole. In studies, it was found that the interaction of Orungal with rifampicin, rifabutin and phenytoin causes the bioavailability of itraconazole and hydroxy-itraconazole to decrease significantly, which leads to a significant decrease in the effectiveness of the drug. The simultaneous use of itraconazole with these drugs, which are potential inducers of hepatic enzymes, is not recommended. No interaction studies with other hepatic enzyme inducers such as carbamazepine, phenobarbital, and isoniazid have been conducted, however, similar results can be suggested. Since itraconazole is mainly metabolized by CYP3A4 isoenzyme, potential inhibitors of this enzyme (ritonavir, indinavir, clarithromycin, and erythromycin, and erythromycin;) of itraconazole. The effect of itraconazole on the metabolism of other drugsItraconazole can inhibit the metabolism of drugs metabolized by isofe ment CYP3A4. The result of this may be an increase or prolongation of their action (including side effects). Before you start taking concomitant medications, you should consult with your doctor about the metabolic pathways of this drug, indicated in the instructions for medical use. After cessation of treatment, plasma concentrations of itraconazole decrease 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 concomitant drugs. When administering a course of Orungal, one should not prescribe: - terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levometadone, which can be used with Orungal, 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 such as pirouette (torsade de pointes); - midazolam To ingestion and triazolam; - metabolized by CYP3A4 enzyme HMG-CoA reductase inhibitors such as simvastatin and lovastatin; - ergot alkaloid drugs such as dihydroergotamine, ergometrine,ergotamine and methylergometrine; - calcium channel blockers - in addition to the possible pharmacokinetic interaction associated with the common metabolic pathway involving the CYP3A4 enzyme, calcium channel blockers have a negative inotropic effect, which can enhance the similar effect of itraconazole. If you are also taking it with Orungal, you should follow the levels in plasma, action, side effects of oral anticoagulants; HIV protease inhibitors (such as ritonavir, indinavir, saquinavir); some anticancer drugs (such as the Vinca roseal alkaloids, busulfan, docetaxel, trimetrexate); CYP3A4 isoenzyme-metabolized by calcium channel blockers (dihydropyridine and verapamil); some immunosuppressive drugs (such as cyclosporine, tacrolimus, sirolimus); certain CYP3A4 enzyme-metabolized HMG-CoA reductase inhibitors, such as atorvastatin; some corticosteroids, such as budesonide, dexamethasone and methylprednisolone; as well as digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam (w / w), rifabutin, methylprednisolone, ebastine, reboxetine, repaglinide, disopyramide, cilostazol, eletriptan, halo gafastamone, halopatoline, repaglinide, disopyramide, cilostazol, eletriptan, haloflufthinone, ebastine, reboxetine, repaglinide, disopyramide, cilostazol, eletriptan, halophasin, ebastine, reboxetine, repaglinide, disopyramide; With simultaneous use with Orungal, the dose of the above preparations should be reduced if necessary. Interactions between itraconazole and zidovudine and fluvastatin were not detected. It was not noted that itraconazole had an effect on ethinyl estradiol and norethisetron metabolism. The effect on protein binding did not show any in vitro studies due to competition due to competition. binding to plasma proteins between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, indomethacin, butamid and sulfamethazine.
special instructions
In the study of the dosage form of the drug Orungal for iv injection, carried out on healthy volunteers, a transient asymptomatic decrease in the left ventricular ejection fraction was noted, 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.Reported cases of congestive heart failure associated with taking Orungal, in connection with which the drug should not be taken in patients with chronic heart failure or with the presence of the disease in history, except when possible benefits far outweigh the potential risk. In an individual assessment of the balance between benefits and risks, factors such as the seriousness of the indications, the dosing regimen and individual risk factors for congestive heart failure should be taken into account. Risk factors include the presence of heart disease such as IHD or valvular heart disease; serious lung diseases such as obstructive pulmonary lesions; renal failure or other diseases associated with edema. Such 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. When they appear, Orungal should be discontinued. When simultaneously taking itraconazole and calcium channel blockers, care should be taken. When the acidity of the gastric juice is low, the absorption of itraconazole is impaired. Patients taking antacid medications (for example, aluminum hydroxide) are recommended to use them no earlier than 2 hours after taking Orungal. For patients with achlorhydria or using histamine H2-receptor blockers or proton pump inhibitors, it is recommended to take the capsules with a Coke. 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 disease, or were treated with itraconazole for systemic indications, or had other serious diseases, as well as in patients who received other drugs that have a hepatotoxic effect. Some patients did not identify obvious risk factors for liver damage. Several 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 Orungal. Patients should be warned about the need to immediately inform the doctor in case of symptoms that suggest the occurrence of hepatitis (anorexia, nausea, vomiting, weakness, abdominal pain and darkening of the urine). In the event of such symptoms, it is necessary to immediately discontinue therapy and conduct a study of the function of the liver. Patients with elevated levels of liver enzymes or liver disease in the active phase, or if toxic liver damage is tolerated while taking other drugs, should not be prescribed Oruungal treatment 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. In patients with impaired liver function and / or kidney function, the drug is used under the control of plasma level of itraconazole and, if necessary, Orungal dose adjustment is performed. It is not recommended to prescribe Orungal in the form of capsules to start treatment of systemic mycoses that pose a threat to the lives of patients. The attending physician should assess the need for the appointment of supportive care for AIDS patients, previously treated for systemic fungal infections, for example, sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and non-meningeal), which have a risk of recurrence. cross hypersensitivity to itraconazole and other azole antifungal drugs. Use in pediatricsSince there are not enough clinical data on the use of Orungal in children, it is not recommended uetsya appoint his children, except in cases where the expected benefit exceeds the possible risk.Vliyanie on the ability to drive vehicles and management mehanizmamiPriem Orungal no effect on the ability to drive and operate machinery.