Itraconazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ITRAZONAZOLE (ITRACONAZOLE)

Composition:

active substance: itraconazole;

1 capsule contains 100 mg of itraconazole (in the form of enteric-coated pellets);

excipients: sugar, hypromellose, Eudragit (E 100), polyethylene glycol 20000;

capsule shell composition: gelatin, titanium dioxide (E 171), indigo carmine (E 132).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size № 0, with a blue cap and a white body, containing white or almost white spherical granules.

Pharmacotherapeutic group.

Antifungal agents for systemic use. ATC code J02A C02.

Pharmacological Properties

Pharmacodynamics

Itraconazole is a triazole derivative with a broad spectrum of activity. In vitro studies have demonstrated that itraconazole inhibits ergosterol synthesis in fungal cells. Ergosterol is an essential component of the fungal cell membrane; inhibition of its synthesis underlies the antifungal effect.

Breakpoint values for itraconazole have been established only for Candida spp. For superficial fungal infections (CLSI M27-A2), breakpoint values have not been defined by EUCAST methodology. The CLSI breakpoint values are as follows: susceptible ≤0.125 μg/mL; dose-dependent susceptible 0.25–0.5 μg/mL; and resistant ≥1 μg/mL. Breakpoint values have not been established for filamentous fungi.

In vitro studies have shown that itraconazole inhibits the growth of a wide range of fungi pathogenic to humans at concentrations usually ≤1 μg/mL. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis, and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis; Pseudallescheria boydii; Penicillium marneffei; and other yeast and mold species.

Candida krusei, Candida glabrata, and Candida tropicalis are generally the least susceptible Candida species, and some isolates exhibit in vitro resistance to itraconazole.

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

Resistance to azoles develops slowly and is usually the result of multiple genetic mutations. Known mechanisms include overexpression of ERG11, which encodes 14α-demethylase (the target enzyme), point mutations in ERG11 leading to reduced affinity of 14α-demethylase for itraconazole, and/or overexpression of efflux transporters, resulting in increased export of itraconazole from fungal cells (thus removing it from its target site). Cross-resistance among azole-class drugs has been observed within Candida species; however, resistance to one azole does not necessarily imply resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics

General Pharmacokinetic Characteristics

Peak plasma concentration after oral administration of itraconazole is reached within 2 to 5 hours. Due to non-linear pharmacokinetics, itraconazole accumulates in plasma with repeated dosing. Steady-state concentrations are typically achieved within 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL, and 2.0 μg/mL after doses of 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal elimination half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34–42 hours after multiple doses. After discontinuation of treatment, itraconazole concentrations decline to nearly undetectable levels in plasma within 7–14 days, depending on the dose and duration of therapy. The mean plasma clearance of itraconazole after intravenous administration is 278 mL/min. Due to saturable hepatic metabolism at higher doses, the clearance of itraconazole decreases.

Absorption

Itraconazole is rapidly absorbed after oral administration. Maximum plasma concentrations of unchanged drug are reached within 2–5 hours following oral administration of capsules. The absolute bioavailability of itraconazole is 55%. Maximum bioavailability is observed when the drug is administered immediately after a high-fat meal.

Absorption of itraconazole capsules is reduced in patients with decreased gastric acidity, those taking acid-suppressing agents (H2-receptor antagonists, proton pump inhibitors), or in patients with achlorhydria due to certain diseases (see sections «Special Warnings and Precautions for Use» and «Interaction with Other Medicinal Products and Other Forms of Interaction»). Absorption of itraconazole on an empty stomach in such patients increases if itraconazole is administered with acidic beverages (e.g., non-diet cola). After administration of a single 200 mg dose of itraconazole on an empty stomach with non-diet cola following ranitidine (an H2-receptor antagonist), absorption of itraconazole was comparable to that observed after administration of itraconazole alone.

The concentration of itraconazole after administration of capsules is lower than after administration of the oral solution at the same dose (see section «Special Warnings and Precautions for Use»).

Distribution

The majority of itraconazole is bound to plasma proteins (99.8%), with albumin being the primary binding component (99.6% for the hydroxymetabolite). It also has high affinity for lipids. Only 0.2% of itraconazole in blood remains unbound. The apparent volume of distribution of itraconazole is very large (>700 L), suggesting extensive tissue distribution: concentrations in the lungs, kidneys, liver, bones, stomach, spleen, and muscles were 2–3 times higher than plasma concentrations. Accumulation of itraconazole in keratinous tissues, particularly skin, was four times higher than in plasma. Concentrations in cerebrospinal fluid are significantly lower than in plasma, but efficacy against infections localized in the cerebrospinal fluid has been demonstrated.

Biotransformation

Itraconazole is extensively metabolized in the liver, forming numerous metabolites. In vitro studies indicate that CYP3A4 is the primary enzyme involved in itraconazole metabolism. The main metabolite is hydroxy-itraconazole, which exhibits antifungal activity in vitro comparable to that of itraconazole. Plasma concentrations of hydroxy-itraconazole are approximately twice those of itraconazole.

Excretion

Approximately 35% of itraconazole is excreted as inactive metabolites in urine and about 54% in feces within one week after administration of the oral solution. Renal excretion of unchanged itraconazole and its active metabolite hydroxy-itraconazole after intravenous administration accounts for less than 1% of the dose. Fecal excretion of unchanged drug varies between 3% and 18%.

Special Patient Populations

Hepatic Impairment

Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole (1 × 100 mg capsule) was conducted in 6 healthy volunteers and 12 patients with cirrhosis. A statistically significant reduction in mean Cmax (by 47%) and a doubling of the elimination half-life (37±17 vs. 16±5 hours) were observed in cirrhotic patients compared to healthy volunteers. However, total itraconazole concentrations, based on AUC, were comparable between the two groups.

There are no available data on long-term use of itraconazole in patients with cirrhosis.

Renal Impairment

Data on the use of oral itraconazole in patients with impaired renal function are limited. A pharmacokinetic study using a single 200 mg dose of itraconazole (4 × 50 mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7, hemodialysis: n=7, chronic ambulatory peritoneal dialysis: n=5). In patients with uremia (mean creatinine clearance 13 mL/min × 1.73 m²), AUC-based concentrations were slightly reduced compared to healthy subjects. The study did not demonstrate any significant effect of hemodialysis or chronic ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, AUC0–8h). Plasma concentration-time profiles showed considerable inter-subject variability in all three groups.

After a single intravenous dose, mean terminal elimination half-lives in patients with mild (CrCl 50–79 mL/min), moderate (CrCl 20–49 mL/min), and severe (CrCl <20 mL/min) renal impairment were similar to those in healthy volunteers (range 42–49 hours vs. 48 hours in patients with renal impairment and healthy volunteers, respectively). Total itraconazole concentrations based on AUC were reduced in patients with moderate and severe hepatic impairment (by 30% and 40%, respectively) compared to healthy volunteers.

There are no available data on long-term use of itraconazole in patients with renal impairment. Dialysis does not affect the elimination half-life or clearance of itraconazole or hydroxy-itraconazole.

Pediatric Population

Data on the use of oral itraconazole in children are limited. Clinical pharmacokinetic studies in children and adolescents aged 5 months to 17 years have been conducted using itraconazole capsules, oral solution, and intravenous solution. Doses with capsules and oral solution ranged from 1.5 to 12.5 mg/kg/day, administered once or twice daily. Intravenous doses were either a single infusion of 2.5 mg/kg or 2.5 mg/kg infused once or twice daily. No significant age dependence of itraconazole AUC or total clearance was observed; however, a weak relationship between age, volume of distribution, Cmax, and terminal elimination was noted. Apparent clearance and volume of distribution were body weight-dependent.

Clinical characteristics.

Indications.

Vulvovaginal candidiasis;

• Lichen planus;
• Dermatomycoses caused by itraconazole-sensitive pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), for example, tinea pedis, tinea cruris, tinea corporis, tinea manuum;
• Oropharyngeal candidiasis;
• Onychomycoses caused by dermatophytes and/or yeasts;
• Histoplasmosis;
• Systemic mycoses (in cases when first-line antifungal therapy cannot be used or when treatment with other antifungal agents is ineffective, which may be due to underlying pathology, pathogen resistance, or drug toxicity);
• Aspergillosis and candidiasis;
• Cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with central nervous system cryptococcosis;
• Maintenance therapy in AIDS patients to prevent recurrence of existing fungal infection.

Itraconazole is also indicated for prophylaxis of fungal infections in patients with prolonged neutropenia when standard therapy is insufficient.

Contraindications.

Itraconazole capsules are contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.

Concomitant use of itraconazole and CYP3A4 substrates is contraindicated. Concurrent administration may increase plasma concentrations of these drugs, potentially leading to enhanced or prolonged therapeutic and adverse reactions, including life-threatening conditions. For example, elevated concentrations of these drugs may result in QT interval prolongation and ventricular tachyarrhythmias, including cases of ventricular fibrillation and potentially fatal arrhythmias. These drugs are listed in the section «Interaction with other medicinal products and other forms of interactions».

Itraconazole capsules are contraindicated in patients with ventricular dysfunction, such as congestive heart failure, or a history of congestive heart failure, except for the treatment of life-threatening infections (see section «Special precautions for use»).

Itraconazole capsules should not be used during pregnancy, except for the treatment of life-threatening conditions in the mother (see section «Use during pregnancy or lactation»).

Interaction with other medicinal products and other forms of interactions.

Itraconazole is predominantly metabolized by cytochrome CYP3A4. Other drugs that are metabolized via this pathway or that modulate CYP3A4 activity may affect the pharmacokinetics of itraconazole. Conversely, itraconazole may also affect the pharmacokinetics of other substances. Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein. When used concomitantly with other drugs, the prescribing information for these drugs should also be consulted regarding metabolic pathways and potential need for dose adjustments.

Medicinal products that may reduce itraconazole plasma concentrations

Medicinal products that reduce gastric acidity (acid-neutralizing agents such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) affect the absorption of itraconazole from capsules. Caution should be exercised when co-administering the following medicinal products with itraconazole capsules:

• When itraconazole is used concomitantly with agents that reduce gastric acidity, itraconazole capsules should be taken with acidic beverages, such as non-diet cola;
• Acid-neutralizing agents (e.g., aluminum hydroxide) should be administered at least 1 hour before or 2 hours after itraconazole capsule administration;
• Antifungal activity should be monitored, and the itraconazole dose increased if necessary.

Concomitant use of itraconazole with potent inducers of the CYP3A4 enzyme results in reduced bioavailability of itraconazole and hydroxy-itraconazole, leading to significantly decreased treatment efficacy. These medicinal products include:

• Antibacterials: isoniazid, rifabutin (also listed in the subsection «Medicinal products whose plasma concentrations are increased by itraconazole»), rifampicin;
• Anticonvulsants: carbamazepine (also listed in the subsection «Medicinal products whose plasma concentrations are increased by itraconazole»), phenobarbital, phenytoin;
• Antivirals: efavirenz, nevirapine.

Concomitant use of potent CYP3A4 enzyme inducers with itraconazole is not recommended. Initiation of the above-mentioned drugs should be avoided 2 weeks before, during, and for 2 weeks after itraconazole treatment, except when potential benefit clearly outweighs the potential risk. Antifungal activity should be closely monitored, and the itraconazole dose increased if necessary.

Medicinal products that increase itraconazole plasma concentrations

Potent inhibitors of the CYP3A4 enzyme may increase itraconazole bioavailability. Examples include:

• Antibacterials: ciprofloxacin, clarithromycin, erythromycin;
• Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, ritonavir (also listed in the subsection «Medicinal products whose plasma concentrations are increased by itraconazole»).

These drugs should be used with caution concomitantly with itraconazole. Such patients should be closely monitored for signs or symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose should be reduced if necessary. Monitoring of itraconazole plasma concentrations is recommended.

Medicinal products whose plasma concentrations are increased by itraconazole

Itraconazole and its main metabolite hydroxy-itraconazole may inhibit the metabolism of drugs metabolized by the CYP3A4 enzyme and P-glycoprotein-mediated drug transport, potentially leading to increased plasma concentrations of these drugs and/or their metabolites. Such increased plasma concentrations may result in enhanced or prolonged therapeutic effects and the occurrence of adverse reactions. Concomitant administration of itraconazole with drugs that are metabolized by CYP3A4 and prolong the QT interval is contraindicated, as this may lead to ventricular tachyarrhythmias, including cases of fatal ventricular fibrillation. After discontinuation of treatment, itraconazole concentrations decrease to nearly undetectable levels in plasma within 7 to 14 days, depending on dose and duration of treatment. In patients with liver cirrhosis or in patients concurrently using CYP3A4 enzyme inhibitors, discontinuation of the drug should be gradual. This is particularly important for medicinal products whose metabolism is affected by itraconazole.

Concomitant medicinal products are grouped into the following categories:

Contraindicated: Under no circumstances should these drugs be used concomitantly or within 2 weeks after completion of itraconazole treatment.

Not recommended: Concomitant use of these medicinal products during and for 2 weeks after discontinuation of itraconazole treatment should be avoided, except when the benefit of treatment outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be closely monitored for signs or symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

Use with caution: Careful monitoring is recommended when these drugs are used concomitantly with itraconazole. Such patients should be closely observed for signs or symptoms of increased or prolonged pharmacological effect of itraconazole, and the itraconazole dose should be reduced if necessary. Monitoring of itraconazole plasma concentration is recommended.

Examples of drugs whose concentrations are increased when used concomitantly with itraconazole are listed in the table with corresponding recommendations.

a See also "Medicinal products that decrease itraconazole plasma concentrations."

b See also "Medicinal products that increase itraconazole plasma concentrations."

Medicinal products whose concentrations are decreased by itraconazole.

Concomitant administration of itraconazole with meloxicam reduces the latter's concentration. Meloxicam should be used with caution when administered concomitantly with itraconazole, and therapeutic or adverse effects should be monitored. Dose adjustment of meloxicam is recommended.

Children.

Studies on drug interactions have been conducted only in adult volunteers.

Special precautions for use.

Cross-sensitivity.

There are no data on cross-sensitivity between itraconazole and other azole antifungal agents. Caution should be exercised when prescribing itraconazole to patients with hypersensitivity to other azoles.

Effect on the heart.

In studies of intravenous itraconazole in healthy volunteers, transient asymptomatic decreases in left ventricular ejection fraction were observed; these returned to baseline before the next infusion. The clinical significance of these findings for oral formulations is not established.

It is known that itraconazole exerts a negative inotropic effect, and cases of congestive heart failure associated with itraconazole use have been reported. In spontaneous reports, the incidence of congestive heart failure was higher with a total daily dose of 400 mg compared to reports with lower daily doses. Therefore, the risk of heart failure may increase with the total daily dose of itraconazole.

The drug should not be administered to patients with existing or history of congestive heart failure, except when the expected benefit clearly outweighs the potential risk. In individual benefit/risk assessment, factors such as severity of the indication, dosing regimen and duration of treatment (total daily dose), and individual risk factors for developing congestive heart failure should be considered. These risk factors include pre-existing cardiac conditions such as ischemic heart disease or valvular heart disease; severe lung diseases, such as obstructive lung disorders; renal insufficiency; or other conditions associated with edema. Such patients should be informed about the signs and symptoms of congestive heart failure, treatment should be administered cautiously, and symptoms of heart failure should be monitored. If such symptoms occur during treatment, itraconazole should be discontinued immediately.

Calcium channel blockers may have a negative inotropic effect, which may be potentiated by the same effect of itraconazole. Additionally, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when co-administering itraconazole and calcium channel blockers due to increased risk of congestive heart failure (see section «Interaction with other medicinal products and other forms of interaction»).

Effect on the liver.

Severe hepatotoxicity, including cases of acute liver failure with fatal outcomes, has been reported very rarely during itraconazole treatment. Most of these cases occurred in patients with pre-existing liver disease receiving systemic treatment, those with other serious underlying conditions, and/or those taking other hepatotoxic drugs. In some patients, no obvious risk factors for liver disease were identified. Some of these cases occurred within the first month of treatment, including the first week. Therefore, monitoring of liver function is advisable in patients taking itraconazole. Patients should be informed about the need to seek immediate medical attention if signs or symptoms of hepatitis develop, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. If these symptoms occur, treatment should be discontinued immediately and liver function tests should be performed. Treatment should only be initiated in patients with elevated liver enzymes, active liver disease, or manifestations of hepatotoxicity from other drugs if the expected benefit outweighs the risk of liver injury. In such cases, monitoring of liver enzymes is required.

Reduced gastric acidity.

Absorption of itraconazole is reduced in conditions of low gastric acidity. Patients who are taking drugs that reduce gastric acidity (such as aluminum hydroxide) concurrently with itraconazole should maintain at least a two-hour interval between administrations of these medicinal products. Patients with achlorhydria, for example, those with AIDS or those taking H2-receptor antagonists or proton pump inhibitors, are recommended to take itraconazole with acidic beverages such as cola.

Elderly patients.

Clinical data on the use of itraconazole in elderly patients are limited. Itraconazole should not be used in elderly patients unless the benefit of treatment outweighs the potential risk.

Hepatic impairment.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when administering the drug to this patient population.

Renal impairment.

Data on the use of oral itraconazole in patients with renal impairment are limited. Caution should be exercised when administering the drug to this patient population. The bioavailability of itraconazole after oral administration may be reduced in patients with renal insufficiency. In such cases, dose adjustment should be considered.

Hearing loss.

Cases of temporary or permanent hearing loss have been reported in patients receiving itraconazole. In some cases, hearing loss occurred concomitantly with quinidine, which is contraindicated (see section «Interaction with other medicinal products and other forms of interaction»). Hearing usually recovers after discontinuation of itraconazole therapy; however, in some patients, hearing loss is irreversible.

Immunocompromised patients.

In some immunocompromised patients (e.g., patients with neutropenia, AIDS, or organ transplant recipients), the oral bioavailability of itraconazole may be reduced.

Patients with life-threatening systemic fungal infections.

Due to its pharmacokinetic properties (see section «Pharmacokinetics»), itraconazole is not recommended for primary therapy of life-threatening conditions caused by systemic fungal infections.

Patients with AIDS.

In patients with AIDS who have been treated for systemic fungal infections such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (meningeal or non-meningeal) and who are at risk of relapse, the physician should evaluate the need for maintenance therapy.

Neuropathy.

If neuropathy associated with itraconazole use occurs, treatment should be discontinued.

Carbohydrate metabolism disorders.

This medicinal product should not be administered to patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Cross-resistance.

If systemic candidiasis is suspected to be caused by Candida species resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, susceptibility testing should be performed before initiating itraconazole treatment.

Interaction potential.

Itraconazole may clinically significantly interact with other medicinal products (see section «Interaction with other medicinal products and other forms of interaction»). Itraconazole should not be administered earlier than two weeks after discontinuation of treatment with CYP3A4 inducers (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, St. John’s wort (Hypericum perforatum)). Concurrent use of itraconazole with these drugs may result in subtherapeutic plasma concentrations of itraconazole and, consequently, ineffective treatment.

Use during pregnancy or breastfeeding.

Pregnancy

Itraconazole should not be prescribed during pregnancy, except in life-threatening systemic mycoses when the potential benefit to the mother outweighs the risk of adverse effects on the fetus (see section «Contraindications»).

Reproductive toxicity of itraconazole has been demonstrated in animal studies.

Data on the use of itraconazole during pregnancy are limited. During the post-marketing period, cases of developmental abnormalities have been reported. These cases included skeletal malformations, genitourinary tract malformations, cardiovascular system malformations, eye abnormalities, chromosomal abnormalities, and multiple congenital malformations. A causal relationship with itraconazole has not been established.

Epidemiological data on the use of itraconazole in the first trimester of pregnancy (mainly in patients who used it for short-term treatment of vulvovaginal candidiasis) did not show an increased risk of congenital malformations compared to women who did not use teratogenic drugs.

Women of childbearing potential.

Women of childbearing potential who are taking itraconazole should use reliable contraceptive methods throughout the treatment course and until the first menstrual period after completion of treatment.

Lactation (breastfeeding).

Very small amounts of itraconazole pass into breast milk. Therefore, during breastfeeding, the potential risk to the infant should be weighed against the expected benefit of itraconazole treatment for the mother. In cases of uncertainty, the woman should discontinue breastfeeding.

Ability to drive and use machines.

No studies on the effect on the ability to drive or operate machinery have been conducted. The possibility of adverse reactions such as dizziness, visual disturbances, and hearing loss (see section «Adverse reactions») should be considered, as these may impair the ability to drive or operate machinery.

Administration and dosage.

Itraconazole should be administered orally immediately after a meal to ensure maximum drug absorption. Capsules should be swallowed whole.

The treatment regimens for adults for each indication are as follows:

The duration of treatment for systemic fungal infections should be adjusted according to the mycological and clinical response to therapy:

Elderly patients.

The use of itraconazole in elderly patients is not recommended (see section «Special instructions»).

Patients with renal impairment.

The bioavailability of the drug after oral administration may be reduced in patients with renal insufficiency; dose adjustment should be considered (see section «Special instructions»).

Patients with hepatic impairment.

Itraconazole is predominantly metabolized in the liver. The terminal half-life of itraconazole is somewhat prolonged in patients with liver cirrhosis. Oral bioavailability is slightly reduced in patients with cirrhosis. Dose adjustment should be considered (see section «Special instructions»).

Children.

The use of itraconazole in children is not recommended (see section «Special instructions»).

Overdose.

There have been no reports of overdose.

Treatment. In case of accidental overdose, supportive measures should be taken. Gastric lavage should be performed within the first hour after oral intake. Activated charcoal may be administered if indicated. Itraconazole cannot be removed by hemodialysis. There is no specific antidote.

Adverse Reactions

The most common adverse reactions were those of gastrointestinal, dermatological, and hepatic origin.

Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare – leukopenia;

Not known – neutropenia, thrombocytopenia.

Immune system disorders:

Uncommon – hypersensitivity;

Not known – anaphylactic, anaphylactoid reactions, angioedema, serum sickness.

Metabolism and nutrition disorders:

Not known – hypokalemia, hypertriglyceridemia.

Nervous system disorders:

Uncommon – headache, dizziness, paresthesia;

Rare – hypesthesia;

Not known – peripheral neuropathy.

Eye disorders:

Rare – visual disturbances;

Not known – blurred vision, diplopia.

Ear and labyrinth disorders:

Rare – tinnitus;

Not known – temporary or permanent hearing loss.

Cardiac disorders:

Not known – congestive heart failure.

Respiratory system disorders:

Rare – dyspnea;

Not known – pulmonary edema.

Gastrointestinal disorders:

Common – abdominal pain, nausea;

Uncommon – vomiting, diarrhea, constipation, dyspepsia, dysgeusia, flatulence;

Rare – pancreatitis.

Hepatobiliary disorders:

Uncommon – hyperbilirubinemia, increased alanine aminotransferase, aspartate aminotransferase levels;

Rare – increased liver enzymes;

Not known – acute liver failure, hepatitis, hepatotoxicity.

Skin and subcutaneous tissue disorders:

Common – rash;

Uncommon – urticaria, alopecia, pruritus;

Not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity.

Musculoskeletal and connective tissue disorders:

Not known – myalgia, arthralgia.

Renal and urinary disorders:

Rare – polyuria;

Not known – urinary incontinence.

Reproductive system and breast disorders:

Uncommon – menstrual disorders;

Not known – erectile dysfunction.

General disorders and administration site conditions:

Uncommon – edema;

Rare – pyrexia.

Shelf life.

3 years.

Storage conditions.

Store in a dry, light-protected, and child-resistant place at a temperature not exceeding 25 °C.

Packaging.

4 capsules in a blister pack, 1 blister pack in a cardboard box;

15 capsules in a blister pack, 1 or 2 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

TOB "Pharma Life"

Manufacturer's address and place of business.

2 D. Apostola Street, Lviv, 79040, Ukraine.

Marketing Authorization Holder.

TOB "Pharma Life"

Address of the Marketing Authorization Holder.

2 D. Apostola Street, Lviv, 79040, Ukraine.