Orungamine, 100 mg, capsules, combi-pack 1+1, 42 pcs.
Effect on cardiac activity: in studies of the dosage form of itraconazole solution for intravenous administration, a transient asymptomatic decrease in left ventricular ejection fraction was noted, which returned to normal before the next infusion. The clinical significance of these data for oral dosage forms is unknown. Itraconazole has a negative inotropic effect. Cases of chronic heart failure associated with itraconazole 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. Orungamin® 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 indication, dosage regimen and individual risk factors for heart failure (coronary heart disease, valvular disease, obstructive pulmonary disease, renal failure and other diseases accompanied by edema) should be taken into account. Such patients should be informed about the signs and symptoms of chronic heart failure and monitored for their occurrence during the course of therapy. If such signs appear, taking Orungamine® should be stopped.
Life-threatening cardiac arrhythmias and/or sudden death have been reported in patients receiving methadone concomitantly.
Drug interactions: Concomitant use of certain drugs with itraconazole may result in changes in the effectiveness of itraconazole and/or concomitant drugs, life-threatening adverse reactions and/or sudden death. Drugs that should not be taken concomitantly with itraconazole, are not recommended for concomitant use, and/or are recommended for concomitant use with itraconazole with caution are listed in the Interactions with Other Drugs section.
Cross-hypersensitivity: Data regarding the presence of cross-hypersensitivity between itraconazole and other azole antifungals are limited. If hypersensitivity to other azoles is present, itraconazole should be prescribed with caution.
Interchangeability: The interchangeable use of itraconazole capsule and itraconazole oral solution is not recommended due to the fact that exposure to itraconazole is higher when administered in oral solution form than in capsule form, even when taking the same doses of itraconazole.
Reduced acidity of gastric juice: with reduced acidity of gastric juice, the absorption of itraconazole from capsules is impaired. Patients with reduced gastric acidity due to disease (for example, in patients with achlorhydria) or due to medications (for example, drugs that suppress ventricular secretion) are recommended to take Orungamin®; in capsules at the same time as acidic drinks (such as non-diet cola). The antifungal activity of the drug should be monitored and the dose of itraconazole should be increased if necessary.
Effect on liver function: In very rare cases, severe toxic liver damage has occurred with the use of itraconazole, 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 severe diseases for whom the drug was prescribed for the treatment of systemic diseases, and 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 therapy. 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, treatment should be stopped immediately and liver function testing should be performed. 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 Orungamine® 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 the concentrations of itraconazole in the blood plasma and, if necessary, adjust the dose of the drug.
Renal impairment: Data on the use of the drug in patients with impaired renal function are limited; in some patients with impaired renal function, exposure to itraconazole may be reduced. Therefore, such patients should be prescribed the drug with caution. It is recommended to monitor the concentrations of itraconazole in the blood plasma 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, those with AIDS, or those undergoing organ transplantation.
Patients with systemic fungal infections that pose a threat to life: due to the pharmacokinetic characteristics of the drug Orungamin® in capsule form, its use is not recommended for the initiation of treatment of systemic mycoses that pose a threat to life in patients.
Patients with AIDS: The physician should evaluate the need for maintenance therapy in patients with AIDS previously treated for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and nonmeningeal), and who are at risk of relapse.
Use in pediatric practice: since there is insufficient clinical data on the use of itraconazole in children, it is recommended to prescribe the drug to children only if the possible benefits of treatment outweigh the potential risks.
Women of childbearing age taking Orungamin® must use adequate methods of contraception throughout the entire course of therapy until the onset of the first menstruation after its completion.
Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Orungamine®, capsule.
In systemic candidiasis suspected to be caused by fluconazole-resistant Candida strains, sensitivity to itraconazole cannot be assumed, and it is therefore recommended to test sensitivity before initiating itraconazole therapy.
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 (see sections “Contraindications”, “Interaction with other drugs”). Hearing is usually restored after treatment with the drug is completed, but in some patients, hearing loss is irreversible.
Fertility: Animal studies have not shown reproductive toxicity with itraconazole.
Cystic fibrosis: In patients with cystic fibrosis, variability in itraconazole plasma concentrations was observed when itraconazole oral solution was administered at a dose of 2.5 mg/kg twice daily. As a result, the therapeutic equilibrium concentration of itraconazole in blood plasma may not be achieved. Steady-state concentrations greater than 250 ng/mL were achieved in approximately 50% of patients over 16 years of age and were not achieved in any patient under 16 years of age. If there is no response to therapy with Orungamin®, capsules, switching to alternative therapy should be considered.
Impact on the ability to drive vehicles and operate machinery
Studies have not been conducted to study the effect of the drug Orungamin® on the ability to drive vehicles and operate machinery. It is necessary to take into account the possibility of adverse reactions, such as dizziness, blurred vision or hearing loss (see section "Side effects"). If the described adverse reactions occur, you should refrain from performing these activities.
Orungamin
Medicines that affect the absorption of itraconazole
Medicines that reduce gastric acidity interfere with the absorption of itraconazole, which is associated with the solubility of the capsule shells.
Medicines that affect the metabolism of itraconazole
Itraconazole is mainly metabolized with the participation of the CYP3A4 isoenzyme. When used simultaneously with rifampicin, rifabutin, phenytoin, which are powerful inducers of the CYP3A4 isoenzyme, the bioavailability of itraconazole and hydroxyitraconazole is significantly reduced, 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 microsomal liver enzymes, is not recommended.
Potent CYP3A4 inhibitors such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.
Effect of itraconazole on the metabolism of other drugs
Itraconazole may inhibit the metabolism of drugs that are substrates of CYP3A isoenzymes. The result of this may be an increase or prolongation of their action, including side effects. When using concomitant medications, it is necessary to study information regarding their metabolism. After cessation of treatment, plasma concentrations of itraconazole decrease gradually depending on the dose and duration of treatment (see section "Pharmacokinetics"). This should be taken into account when assessing the inhibitory effect of itraconazole on the metabolism of concomitantly prescribed drugs.
Medicines that are not recommended to be prescribed concomitantly with itraconazole
:
- terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levacetylmethadol, HMG-CoA reductase inhibitors such as simvastatin and lovastatin;
- oral midazolam and triazolam;
- ergot alkaloid preparations such as dihydroergotamine, ergometrine, ergotamine and methylergometrine;
- nisoldipine;
- Slow calcium channel blockers may have a negative inotropic effect, which is enhanced when taken concomitantly with itraconazole. Caution must be exercised when taking itraconazole and slow calcium channel blockers concomitantly, since the metabolism of slow calcium channel blockers may be reduced.
Drugs, when administered concomitantly, it is recommended to monitor their plasma concentrations, effects, and side effects
If necessary, the dose of these drugs should be reduced:
- indirect anticoagulants;
- HIV protease inhibitors (ritonavir, indinavir, saquinavir);
- some anticancer drugs (vinca rosea alkaloids, including vincristine and vinblastine; busulfan, docetaxel, trimetrexate);
- blockers of “slow” calcium channels metabolized by the CYP3A4 isoenzyme (verapamil and dihydropyridine derivatives);
- some immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus);
- some HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (atorvastatin);
- some glucocorticosteroids (budesonide, dexamethasone, fluticasone and methylprednisolone);
- digoxin (due to P-glycoprotein inhibition);
- other drugs: carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, intravenous midazolam, rifabutin, ebastine, reboxetine, cilostazol, disopyramide, halofantrine, repaglinide, fentanyl.
No interaction was found between itraconazole, zidovudine and fluvastatin.
There was no effect of itraconazole on the metabolism of ethinyl estradiol and norethisterone.
Effect on protein binding
In vitro studies
demonstrated the absence of interaction between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamerazine when bound to plasma proteins.
