Orungal^® (Capsules, Solution) Instructions for Use

ATC Code

J02AC02 (Itraconazole)

Active Substance

Itraconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

Itraconazole is a synthetic broad-spectrum antifungal agent, a triazole derivative.

The mechanism of action of itraconazole involves the inhibition of ergosterol biosynthesis, a key component of the fungal cell membrane involved in maintaining its structural integrity.

Disruption of ergosterol synthesis leads to altered membrane permeability and cell lysis, which underlies the antifungal effect of itraconazole.

Itraconazole is active against infections caused by fungi: Candida spp. (including Candida albicans, Candida tropicalis, Candida parapsilosis and Candida dubliniensis), Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including Histoplasma capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii and Trichosporon spp.

Itraconazole has also shown activity against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and other yeast and fungal infections.

Candida krusei, Candida glabrata and Candida tropicalis are the Candida species least sensitive to the action of itraconazole.

In vitro, the Candida genus has occasionally shown unequivocal resistance to itraconazole.

The main types of fungi whose growth is not suppressed by itraconazole are Zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

Resistance to azoles develops slowly and is often the result of several genetic mutations.

The described mechanisms of resistance development include hyperexpression of the ERG11 gene, encoding the enzyme 14α-demethylase, which is the primary target of azole action, and point mutations in ERG11, leading to reduced binding of enzymes to azoles and/or activation of transport systems, resulting in increased efflux of azoles.

Cross-resistance of Candida spp. to drugs of the azole group has been observed, although resistance to one drug in this group does not necessarily imply resistance to other azole drugs.

Strains of Aspergillus fumigatus resistant to itraconazole have been reported.

Pharmacokinetics

Itraconazole is rapidly absorbed after oral administration.

The C_max of unchanged itraconazole in plasma is reached within 2-5 hours after oral administration of the capsule.

The absolute bioavailability of itraconazole after oral administration is about 55%.

The binding of itraconazole to plasma proteins is 99.8%, mainly to albumin (hydroxyitraconazole is 99.6% bound to albumin).

An affinity for lipids has also been noted.

Only 0.2% of itraconazole remains unbound in plasma.

The apparent V_d is >700 L, indicating its significant distribution in tissues.

Concentrations in the lungs, kidneys, bones, stomach, spleen, and muscles are 2-3 times higher than the corresponding plasma concentrations, while the concentration in keratin-containing tissues, especially the skin, is approximately 4 times higher than the plasma concentration.

The concentration in the cerebrospinal fluid is significantly lower than in plasma; nevertheless, the efficacy of itraconazole against pathogens present in the cerebrospinal fluid has been demonstrated.

Itraconazole undergoes extensive metabolism by the CYP3A4 isoenzyme in the liver, forming numerous metabolites.

The main metabolite is hydroxyitraconazole, which in vitro has antifungal activity comparable to itraconazole.

Plasma concentrations of hydroxyitraconazole are approximately twice the concentration of itraconazole.

Itraconazole is excreted predominantly as inactive metabolites in the urine (35%) and feces (54%) within one week after taking the oral solution.

Renal excretion of itraconazole and its active metabolite hydroxyitraconazole accounts for less than 1% of the intravenously administered drug dose.

Based on the results of pharmacokinetic studies of ¹⁴C-labeled itraconazole after oral administration, the excretion of unchanged itraconazole in feces varies from 3% to 18% of the administered dose.

Since the redistribution of itraconazole from keratin-containing tissues is negligible, the elimination of itraconazole from these tissues is associated with epidermal regeneration.

Unlike plasma, the concentration of itraconazole in the skin persists for 2-4 weeks after cessation of 4-week treatment, and the concentration in nail keratin, where Itraconazole can be detected as early as 1 week after the start of treatment, persists for at least 6 months after the end of a 3-month course of treatment.

Indications

Lesions of the skin and mucous membranes: vulvovaginal candidiasis, pityriasis versicolor, dermatomycoses, oral mucosal candidiasis, fungal keratitis.

Onychomycosis caused by dermatophytes and/or yeasts.

Systemic mycoses (including systemic aspergillosis, candidiasis).

Cryptococcosis (including cryptococcal meningitis) – in immunodeficient patients and in all patients with CNS cryptococcosis, Itraconazole should be used only if first-line drugs are not applicable in this case or are not effective.

Histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other rare systemic and tropical mycoses.

ICD codes

Dosage Regimen

Capsules

Capsules should be taken immediately after meals, swallowed whole.

The recommended doses of Orungal^® depending on the indications are presented in Table 1.

* – the duration of treatment may be adjusted depending on the clinical effectiveness of the treatment

Solution

For the treatment of oral and/or esophageal candidiasis, Orungal^® is prescribed at 200 mg (2 measuring cups)/day in 1 or 2 doses for 1 week.

If there is no positive effect after 1 week, the course of treatment should be continued for another 1 week.

For the treatment of oral and/or esophageal candidiasis, with resistance to fluconazole, 200-400 mg (2-4 measuring cups)/day in 1-2 doses for 2 weeks is prescribed.

If there is no positive effect after 2 weeks, treatment should be continued for another 2 weeks.

For the prevention of systemic fungal infections, the drug is prescribed at a dose of 5 mg/kg body weight/day in 2 doses.

The drug is started 1 week before the start of cytostatic treatment or one week after bone marrow transplantation and continued until the neutrophil count recovers (at least 1000 cells/μL).

The solution should be taken orally on an empty stomach.

The solution should be swished around in the mouth and then swallowed.

After this, the mouth should not be rinsed with water.

Adverse Reactions

Immune system disorders very rarely – serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.

Metabolism and nutrition disorders very rarely – hypertriglyceridemia.

Nervous system disorders very rarely – tremor.

Eye disorders very rarely – visual disturbances (including blurred vision, diplopia).

Ear and labyrinth disorders very rarely – persistent or temporary hearing loss.

Cardiac disorders very rarely – chronic heart failure.

Respiratory, thoracic and mediastinal disorders often – dyspnea.

Gastrointestinal disorders very rarely – pancreatitis.

Hepatobiliary disorders very rarely – severe toxic liver damage (including several cases of acute liver failure with fatal outcome).

Skin and subcutaneous tissue disorders very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.

Investigations very rarely – increased blood CPK activity.

Contraindications

Hypersensitivity to itraconazole; simultaneous administration of drugs that are substrates of the CYP3A4 isoenzyme, such as levacetylmethadol, methadone, disopyramide, dofetilide, dronedarone, quinidine, telithromycin in patients with severe renal or hepatic impairment, ticagrelor; halofantrine; astemizole, mizolastine, terfenadine, ergot alkaloids: dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), eletriptan, irinotecan, lurasidone, orally administered midazolam, pimozide, sertindole, triazolam, bepridil, felodipine, lercanidipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, domperidone, lovastatin, simvastatin, atorvastatin, fesoterodine in patients with moderate or severe renal or hepatic impairment, solifenacin in patients with severe renal impairment and moderate or severe hepatic impairment, colchicine in patients with hepatic or renal impairment; current or history of chronic heart failure (except for the treatment of life-threatening or other dangerous infections); children under 3 years of age; pregnancy, breastfeeding period.

Concomitant use of itraconazole with drugs that are substrates of the CYP3A4 isoenzyme may increase the plasma concentration of itraconazole, enhance or prolong therapeutic and adverse effects, which may cause a potentially dangerous situation (for example, increased plasma concentrations of some drugs may cause QT interval prolongation and cardiac tachyarrhythmia, including torsades de pointes ventricular arrhythmia.

With caution

Liver cirrhosis, severe hepatic and renal impairment, hypersensitivity to other azoles, elderly patients, children over 3 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in liver cirrhosis, severe hepatic impairment.

In patients with moderate and severe hepatic insufficiency, concomitant use of itraconazole with a number of drugs is contraindicated.

Use in Renal Impairment

Use with caution in severe renal impairment.

In patients with moderate and severe renal insufficiency, concomitant use of itraconazole with a number of drugs is contraindicated.

Pediatric Use

Contraindicated for use in children under 3 years of age.

Since clinical data on the use of itraconazole in children are insufficient, use in children over 3 years of age is recommended only if the potential benefit of treatment outweighs the potential risk.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

In a study of intravenous itraconazole in healthy volunteers, a transient asymptomatic decrease in left ventricular ejection fraction was noted, which normalized before the next itraconazole infusion.

The clinical significance of these findings for oral dosage forms is unknown.

Itraconazole has a negative inotropic effect.

Cases of chronic heart failure associated with itraconazole use have been reported.

With a daily itraconazole dose of 400 mg/day, a more frequent occurrence of heart failure was observed; with lower daily doses, such a pattern was not identified.

The risk of chronic heart failure is presumably proportional to the daily dose.

The drug should not be taken by patients with chronic heart failure or with a history of this symptom complex, except in cases where the potential benefit significantly outweighs the potential risk.

When individually assessing the benefit-risk ratio, factors such as the severity of the indication, dosage regimen, and individual risk factors for heart failure (coronary artery disease, valvular disease, obstructive pulmonary disease, renal failure and other conditions 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 appearance during the course of treatment.

If such signs appear, the drug should be discontinued.

Life-threatening cardiac arrhythmias and/or sudden death have been reported in patients with concomitant use of itraconazole and methadone.

Calcium channel blockers may have a negative inotropic effect, which may be additive to the effect of itraconazole.

Furthermore, Itraconazole may inhibit the metabolism of calcium channel blockers.

Therefore, caution should be exercised when using itraconazole and calcium channel blockers concomitantly due to an increased risk of congestive heart failure.

Concomitant use of certain drugs with itraconazole may lead to changes in the effectiveness of itraconazole and/or the concomitantly used drugs, to the occurrence of life-threatening adverse reactions and/or sudden death.

Drugs that should not be taken concomitantly with itraconazole, not recommended for concomitant use and/or recommended for concomitant use with itraconazole with caution are listed in the “Drug Interactions” section.

Data regarding cross-hypersensitivity between itraconazole and other antifungal agents with an azole structure (from the azole group) are limited.

If there is hypersensitivity to other azoles, Itraconazole should be prescribed with caution.

In very rare cases, severe toxic liver damage developed with the use of itraconazole, including several cases of acute liver failure with fatal outcome.

In most cases, this occurred in patients who already had liver disease, in patients with other serious diseases for whom Itraconazole was prescribed for the treatment of systemic diseases, as well as in patients receiving other drugs with hepatotoxic effects.

However, some patients had no concomitant diseases 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, treatment should be stopped immediately and liver function tests should be performed.

Patients with elevated liver enzymes, active liver disease, or a history of toxic liver damage due to other drugs should not be prescribed itraconazole treatment, except in cases where the expected benefit outweighs the potential risk of liver damage.

It is recommended to monitor liver function laboratory parameters in patients with pre-existing liver dysfunction or patients who have experienced hepatotoxicity from other drugs.

Itraconazole is predominantly metabolized in the liver.

Since in patients with impaired liver function the terminal T_1/2 of itraconazole is somewhat prolonged, it is recommended to monitor itraconazole plasma concentrations and adjust its dose if necessary.

Data on the use of itraconazole in patients with renal impairment are limited; in some patients with renal insufficiency, the exposure to itraconazole may be reduced.

Therefore, such patients should be prescribed the drug with caution.

It is recommended to monitor the plasma concentration of itraconazole and adjust the drug dose if necessary.

The bioavailability of itraconazole upon oral administration may be reduced in some immunocompromised patients, such as those with neutropenia, patients with AIDS, or those who have undergone organ transplantation. Therefore, the dose should be adjusted based on the clinical picture in this group of patients.

Due to the pharmacokinetic characteristics of itraconazole in capsule form, its use is not recommended for initiating treatment of systemic mycoses that are life-threatening to patients.

The treating physician should assess the need for maintenance therapy in HIV-infected patients with AIDS who are at risk of relapse and have previously received treatment for systemic fungal infections.

Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with the intake of itraconazole.

In systemic candidiasis, presumably caused by fluconazole-resistant strains of Candida, sensitivity to itraconazole cannot be assumed; therefore, it is recommended to check susceptibility before initiating itraconazole therapy.

Data on the use of itraconazole in elderly patients are limited. The drug is recommended to be prescribed only if the potential benefit of treatment outweighs the potential risk. In general, when selecting a dose for elderly patients, it is recommended to pay attention to the frequency of decreased liver, kidney, and cardiovascular function, as well as concomitant diseases or other drug therapy.

Temporary or permanent hearing loss has been reported in patients taking Itraconazole. In some cases, hearing loss occurred while taking quinidine concurrently. Hearing usually recovers after the end of itraconazole therapy, but in some patients, the hearing loss is irreversible.

Variability in itraconazole plasma concentrations was observed in patients with cystic fibrosis when using itraconazole oral solution at a dose of 2.5 mg/kg twice daily. As a result, the therapeutic C_ss of itraconazole in plasma may not be achieved. C_ss >250 ng/ml was achieved in approximately 50% of patients over 16 years of age and was not achieved in any patient under 16 years of age. If there is no response to itraconazole capsule therapy, the possibility of switching to alternative therapy should be considered.

Use in pediatrics

Since clinical data on the use of itraconazole in children are insufficient, use in children is recommended only if the potential benefit of treatment outweighs the potential risk.

Effect on the ability to drive vehicles and operate machinery

Studies on the effect of itraconazole on the ability to drive vehicles and operate machinery have not been conducted. The possibility of adverse reactions such as dizziness, visual disturbances, and hearing loss should be taken into account. If the described undesirable reactions occur, one should refrain from performing these activities.

Drug Interactions

Itraconazole has a high potential for drug interactions.

Itraconazole is metabolized primarily by the CYP3A4 isoenzyme. Other substances that use this metabolic pathway or alter the activity of the CYP3A4 isoenzyme may affect the pharmacokinetics of itraconazole. When itraconazole is used concomitantly with moderate and potent inducers of the CYP3A4 isoenzyme, the bioavailability of itraconazole and hydroxyitraconazole may decrease, so efficacy may be reduced. Concomitant use with moderate or potent inhibitors of the CYP3A4 isoenzyme may increase the bioavailability of itraconazole, leading to more pronounced or prolonged pharmacological effects of itraconazole.

The absorption of itraconazole is reduced in patients with reduced gastric acidity. Drugs that reduce gastric acidity impair the absorption of itraconazole from capsules. To counteract this effect, it is recommended to take Itraconazole capsules with an acidic beverage (e.g., non-diet cola) if drugs to reduce gastric acidity are being taken.

Itraconazole and its main metabolite, hydroxyitraconazole, are potent inhibitors of CYP3A4. Itraconazole is an inhibitor of the drug transport molecules P-glycoprotein and Breast Cancer Resistance Protein (BCRP). Itraconazole may inhibit the metabolism of drugs metabolized by the CYP3A4 isoenzyme and the transport of drugs by P-glycoprotein and/or BCRP, which may increase the plasma concentration of these drugs and/or their active metabolites when used concomitantly with itraconazole. Increased plasma concentrations may enhance or prolong both the therapeutic and adverse effects of these drugs. For some drugs, concomitant use with itraconazole may lead to a decrease in the plasma concentration of the drug. As a result, the efficacy of the drugs may be reduced.

After discontinuation of itraconazole therapy, the plasma concentration decreases below the limit of detection within 7-14 days, depending on the dose and duration of therapy. In patients with liver cirrhosis or those receiving CYP3A4 inhibitors, the plasma concentration decreases more slowly. This is particularly important to consider when initiating therapy with drugs whose metabolism is affected by Itraconazole.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.