Instructions for use ORUNGAL
Women of childbearing age taking Orungal® must use adequate methods of contraception throughout the course of treatment until the onset of the first menstruation after its completion.
Effect on cardiac activity:
in a study of the dosage form of the drug Orungal® for intravenous administration, 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 these data for oral dosage forms is unknown.
Itracopazole has a negative inotropic effect. Cases of chronic heart failure associated with taking Orungal® have been reported. At a daily dose of 400 mg of itraconazole, an increased incidence of heart failure was observed; at lower daily doses such a pattern was not revealed. The risk of chronic heart failure is presumably proportional to the daily dose. The drug Orungal® should not be taken by patients with chronic heart failure or with a history of this symptom complex, unless the possible benefit significantly outweighs the potential risk. When individually assessing the balance of benefit and risk, factors such as the severity of the indications, dosage regimen and individual risk factors for heart failure (coronary heart disease, valvular lesions, obstructive pulmonary diseases, renal failure and other diseases accompanied by edema) should be taken into account. Patients should be informed about the signs and symptoms of chronic heart failure and monitored for their occurrence during the course of treatment. If such signs appear, taking Orungal® should be stopped.
Reduced acidity of gastric juice:
with reduced acidity of gastric juice, the absorption of itraconazole from capsules is impaired. Patients taking antacid drugs (for example, 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® with drinks containing cola.
Effect on liver function:
in very rare cases, when using the drug Orungal®, severe toxic liver damage developed, including several cases of acute liver failure with a fatal outcome. In most cases, this occurred in patients who already had liver disease, in patients with other serious diseases for whom the drug was prescribed for the treatment of systemic diseases, as well as in patients receiving other drugs that have hepatotoxic effects. However, some patients had no comorbidities or obvious risk factors for liver damage. Several such cases occurred in the first month of therapy, and some in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy. If symptoms suggestive of hepatitis occur, namely:
- anorexia, nausea, vomiting, weakness, abdominal pain and dark urine, you must immediately stop treatment and conduct a liver function test. Patients with increased activity of liver enzymes or active liver disease, or who have suffered toxic liver damage due to taking other drugs should not be treated with Orungal® unless the expected benefit justifies the risk of liver damage. In such cases, it is necessary to monitor the activity of liver enzymes during treatment. Itraconazole is predominantly metabolized in the liver. Since the total half-life of itraconazole is slightly increased in patients with impaired liver function, it is recommended to monitor itraconazole plasma concentrations and adjust the dose of the drug if necessary.
Renal dysfunction:
Data on the use of the drug in patients with impaired renal function are limited, so such patients should take the drug with caution. It is recommended to monitor plasma concentrations of itraconazole and, if necessary, adjust the dose of the drug.
Immunocompromised patients:
The oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as neutropenic patients, patients with AIDS, or those undergoing organ transplantation.
Patients with life-threatening systemic fungal infections:
Due to the pharmacokinetic characteristics of the drug Orungal® in capsule form is not recommended for starting the treatment of systemic mycoses that pose a threat to the life of patients.
AIDS patients:
The treating physician should evaluate the need for maintenance therapy in patients with AIDS who have previously been treated for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and nonmeningeal), and who are at risk of relapse.
Application in pediatric practice:
Since there is insufficient clinical data on the use of Orungal® in children, it is recommended to prescribe the drug to children only if the possible benefit outweighs the potential risk. It is known that the drug was prescribed to children aged 3 to 16 years at a dosage of 100 mg 1 time / day for the treatment of systemic fungal infections; no side effects were observed.
- Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Orungal® capsules.
- There is no evidence of cross-hypersensitivity to itraconazole and other azole antifungals.
Hearing loss:
Temporary or permanent hearing loss has been reported in patients taking itraconazole. In some cases, hearing loss occurred during concomitant use with quinidine. Hearing is usually restored after completion of therapy with Orungal®, however, in some patients, hearing loss is irreversible.
Impact on the ability to drive a car and operate machinery
Usually, Orungal® does not affect the ability to drive a car or operate machinery, but in rare cases, blurred vision may occur when taking the drug. If this side effect occurs, you should refrain from driving or operating equipment.
Orungal®
In a study of the IV dosage form of the drug Orungal, a transient asymptomatic decrease in left ventricular ejection fraction was noted, which normalized until the next infusion of the drug. The clinical significance of these data for oral dosage forms is unknown.
Itraconazole has a negative inotropic effect. Cases of congestive heart failure associated with taking Orungal have been reported, and therefore the drug should not be taken by patients with congestive heart failure or with a history of this symptom complex, unless the possible benefit significantly outweighs the potential risk. When individually assessing the balance of benefit and risk, the severity of the indications, dosage regimen and risk factors for congestive heart failure should be taken into account. Risk factors include the presence of cardiovascular diseases such as coronary artery disease or heart valve disease; lung diseases such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Treatment with Orungal in this case should be carried out with caution, and 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, inconsistent therapeutic levels of itraconazole were noted when the solution was taken continuously at a dose of 2.5 mg/kg body weight 2 times a day.
In very rare cases, when using Orungal, severe toxic liver damage developed (including cases of acute liver failure with fatal outcome). In most cases, this occurred in patients with existing liver diseases, or in patients to whom the drug was prescribed for the treatment of systemic diseases, with other serious diseases, as well as in patients receiving other drugs that have hepatotoxic effects. Some patients had 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 to seek immediate medical attention if symptoms suggestive of hepatitis (anorexia, nausea, vomiting, weakness, abdominal pain, and dark urine) occur. If such symptoms appear, it is necessary to immediately stop therapy with Orungal and conduct a liver function test. Patients with elevated levels of liver enzymes or active liver disease, or history of liver toxicity due to other medications, should not be prescribed 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.
When prescribing Orungal to patients with impaired liver and kidney function, due to the possibility of reducing the bioavailability of itraconazole, it is recommended 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, Orungal should not be used as initial therapy in patients with severe neutropenia.
If neuropathy occurs caused by taking Orungal solution, treatment should be discontinued.
Since there is insufficient clinical data on the use of Orungal in elderly patients, it is recommended to prescribe itraconazole solution to patients in this age group only if the potential benefit outweighs the possible risk.
Use in pediatrics
Since there is insufficient clinical data on the use of Orungal solution in children, it is recommended to prescribe the drug to children only if the potential benefit outweighs 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 body weight taken 2 times a day. Side effects such as diarrhea, abdominal pain, fever, vomiting, mucositis (inflammation of the oral mucosa) were observed more often in children than in adults. However, it is difficult to reliably establish what is the cause of these adverse reactions (Orungal or concomitantly taken chemotherapy drugs).
Impact on the ability to drive vehicles and operate machinery
Orungal does not have any impact on the ability to drive a car or operate machinery.
Orungal solution for oral administration 10 mg/ml 150 ml bottle 1 pc. in St. Petersburg
Pharmacological action: In vitro
demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, an essential component of the fungal cell membrane.
Active against dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum),
yeast-like fungi
Candida spp.
(including
C.albicans, C.glabrata, C.krusei)
, molds
(Cryptococcus neoformans, Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis),
etc.
The bioavailability of itraconazole ranges from 40–100%, depending on the dosage form and conditions of administration.
The pharmacokinetics of itraconazole after IV administration and its absolute bioavailability when taken orally as a solution were studied in a randomized crossover study in 6 healthy male volunteers; The observed bioavailability when taking the solution orally was 55%. Bioavailability was higher when the solution was taken on an empty stomach: in 27 healthy male volunteers, AUC0–24 h values at equilibrium when taken on an empty stomach were 131 ± 30% of those observed when taken after a meal.
The bioavailability of itraconazole capsules is greatest when the capsules are taken immediately after a heavy meal. In a crossover study in 6 healthy male volunteers receiving itraconazole capsules at a single dose of 100 mg immediately after or without a fast meal, Cmax was 132 ± 67 ng/ml and 38 ± 20 ng/ml, respectively. Absorption of itraconazole on an empty stomach is variable and depends on the level of intragastric acidity (relative or absolute achlorhydria). There was a decrease in bioavailability in patients with AIDS, as well as in volunteers receiving suppressors of gastric secretion (for example, H2-antihistamines) and an increase in absorption when taking itraconazole capsules simultaneously with cola. A crossover study in 18 AIDS patients showed that when taking 200 mg of itraconazole on an empty stomach simultaneously with cola (compared to taking the same amount of water), AUC0–24 values increased by 75±121%, Cmax increased by 95±128%.
Cmax is achieved within 3–4 hours, equilibrium concentration in plasma (when prescribed 100–200 mg 1–2 times a day) - within 15 days and is (3–4 hours after taking the last dose): 0.4 mcg/ ml (when taken 100 mg 1 time per day), 1.1 µg/ml or 2 µg/ml (200 mg 1 or 2 times per day). Plasma protein binding - 99.8% (itraconazole), 99.5% (hydroxyitraconazole). Penetrates into tissues and organs (including the vagina), contained in the secretion of the sebaceous and sweat glands. Accumulates in the lungs, kidneys, liver, bones, stomach, spleen, skeletal muscles (the concentration of itraconazole in these tissues exceeds the plasma concentration by 2–3 times. Concentrations in keratin-containing tissues, especially the skin, are 4 times higher than plasma concentrations. Itraconazole is found in the keratin of nails already 1 week after the start of treatment and persists for at least 6 months after a 3-month course of treatment, in the skin - for 2-4 weeks after a 4-week treatment. Passes poorly through the BBB. Biotransforms in the liver (mainly with the participation CYP3A4) with the formation of a large number of metabolites, including active (hydroxyitraconazole).Excreted by the kidneys (less than 0.03% unchanged, about 40% in the form of inactive metabolites) and with feces (3-18% unchanged In patients with renal failure, bioavailability is slightly reduced compared to patients with normal renal function.In patients with liver cirrhosis, T1/2 is increased.
Decreased cardiac contractility
When intravenously administered itraconazole to anesthetized dogs, a dose-dependent negative inotropic effect was observed. In a study in healthy volunteers, intravenous injections of itraconazole resulted in a transient, asymptomatic decrease in left ventricular ejection fraction (these changes disappeared before the next infusion - 12 hours later).
