Sporaxol capsules 100 mg strip No. 30

Instructions for Sporaxol capsules 100 mg strip No. 30

Composition

active ingredient: itraconazole;

1 capsule contains 100 mg of itraconazole;

excipients: spherical sugar (sucrose, corn starch, purified water), poloxamer 188, hypromellose 6 CP, micronized poloxamer 188, capsule (indigo carmine (E 132), quinoline yellow (E 104), titanium dioxide (E 171), purified water, gelatin).

Dosage form

Capsules.

Main physicochemical properties: opaque hard gelatin capsules No. 0 with a green cap and body, containing yellow-beige spherical microgranules.

Pharmacotherapeutic group

Antifungal drugs for systemic use. Itraconazole. ATX code J02A C02.

Pharmacological properties

Pharmacodynamics

Itraconazole is a triazole derivative with a broad spectrum of activity. In vitro studies have shown that itraconazole inhibits the synthesis of ergosterol in fungal cells. Ergosterol is an important component of the fungal cell membrane, and inhibition of its synthesis provides an antifungal effect.

For itraconazole, breakpoints have only been established for Candida spp. For superficial fungal infections (CLSI M27-A2, breakpoints not established by EUCAST methodology), the CLSI breakpoints are: susceptible ≤0.125; susceptible dose-dependent 0.25–0.5 and resistant ≥1 μg/mL. Breakpoints have not been established for mycelial 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. The spectrum includes: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Candida spp., including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.,), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Coccidiodes immitis, Pseudallescheria boydii, Penicillium marneffei and other species of yeasts and fungi.

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

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

Pharmacokinetics

The pharmacokinetics of itraconazole have been studied in healthy volunteers and special patient populations after single and multiple doses.

Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations after oral administration are reached within 2–5 hours. The absolute bioavailability of itraconazole is 55%. Maximum bioavailability when administered orally is observed when a high-calorie meal is consumed immediately after administration.

Distribution

Itraconazole is largely bound to plasma proteins (99.8%), with albumin being the major binding component (99.6% for the hydroxymetabolite). It also has a high affinity for lipids. Only 0.2% of itraconazole in the blood remains unbound. The apparent volume of distribution of itraconazole is quite large (>700 L), suggesting extensive tissue distribution: concentrations in the lungs, kidneys, liver, bones, stomach, spleen, and muscles were 2–3 times higher than those in plasma. Itraconazole accumulation in keratinous tissues, especially in the skin, was 4 times higher than that in plasma.

Biotransformation

Itraconazole is extensively metabolized in the liver to form a large number of metabolites. One of these metabolites is hydroxy-itraconazole, which has comparable antifungal activity to itraconazole in vitro. Plasma concentrations of hydroxy-itraconazole are approximately 2-fold higher than those of itraconazole.

According to in vitro studies, CYP3A4 is the main enzyme involved in the metabolism of itraconazole.

Breeding

Approximately 35% of itraconazole is excreted as inactive metabolites in the urine and approximately 54% in the feces. Renal excretion of the parent drug is less than 0.03% of the dose, while excretion of unchanged drug in the feces varies from 3 to 18%. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Linearity/nonlinearity

Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after multiple administration. Steady-state concentrations are reached within 15 days, with Cmax and AUC values 4–7 times higher than after a single dose. The mean elimination half-life is 40 hours after repeated doses.

Special categories of patients

Hepatic impairment: A pharmacokinetic study using a single dose of 100 mg itraconazole (1 capsule of 100 mg) was conducted in 6 healthy subjects and 12 cirrhotic subjects. No clinically significant difference in AUC∞ was observed between the two groups. In cirrhotic subjects, a clinically significant decrease in mean Cmax (47%) and a 2-fold increase in the half-life of itraconazole (37±17 vs. 16±5 hours) were observed.

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

Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when using the drug in this category of patients.

Indication

Vulvovaginal candidiasis; lichen planus; dermatophytosis caused by itraconazole-sensitive pathogens (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), e.g. tinea pedis, tinea inguinale, tinea corporis, tinea palmaris; oropharyngeal candidiasis; onychomycoses caused by dermatophytes and/or yeasts; histoplasmosis; systemic mycoses (in cases where first-line antifungal therapy cannot be used, or in case of ineffectiveness of treatment with other antifungal drugs, which may be due to the underlying pathology, insensitivity of the pathogen or toxicity of the drug): aspergillosis and candidiasis; cryptococcosis (including cryptococcal meningitis): treatment of immunocompromised patients with cryptococcosis and all patients with cryptococcosis of the central nervous system; maintenance therapy in patients with AIDS to prevent recurrence of existing fungal infections. Itraconazole is also prescribed for the prevention of fungal infections in patients with prolonged neutropenia in cases where standard therapy is insufficient.

Contraindication

Known hypersensitivity to the active substance or to any of the excipients of the drug.

Concomitant use of itraconazole and CYP3A4 substrates is contraindicated. Concomitant use may result in increased plasma concentrations of these medicinal products, which may lead to increased or prolonged therapeutic and adverse reactions and potentially life-threatening conditions. For example, increased concentrations of these medicinal products may lead to QT prolongation and ventricular tachyarrhythmias, including cases of ventricular fibrillation, arrhythmias with a potentially fatal outcome. These medicinal products are listed in the section “Interaction with other medicinal products and other forms of interaction”.

Use 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 warnings and precautions for use").

The drug should not be used during pregnancy, except for the treatment of life-threatening conditions (see section "Use during pregnancy or breastfeeding"). Women of childbearing potential taking itraconazole capsules should use reliable contraception throughout the course of treatment until the first menstrual period after its completion.

Interaction with other medicinal products and other types of interactions

Itraconazole is primarily metabolized by cytochrome CYP3A4. Other drugs that are metabolized by this pathway or modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. 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 for information on the metabolic pathways and the possible need for dose adjustments.

Drugs that may reduce itraconazole plasma concentrations

Medicines that reduce stomach acidity (acid-neutralizing medicines such as aluminium hydroxide or acid-suppressing medicines such as H2-receptor antagonists and proton pump inhibitors) affect the absorption of itraconazole from the capsules. Caution should be exercised when using the following medicines and itraconazole capsules at the same time:

When itraconazole and antacids are used concomitantly, itraconazole capsules should be taken with acidic beverages, such as non-diet cola; antacids (e.g., aluminum hydroxide) should be taken at least 1 hour before or 2 hours after itraconazole capsules; antifungal activity should be monitored and the dose of itraconazole increased if necessary.

Concomitant use of itraconazole with potent CYP3A4 enzyme inducers leads to a decrease in the bioavailability of itraconazole and hydroxy-itraconazole, resulting in a significant reduction in the effectiveness of treatment. For example:

antibacterials: isoniazid, rifabutin (see also below "Medicines whose plasma concentration is increased by itraconazole"), rifampicin; anticonvulsants: carbamazepine (see also below "Medicines whose plasma concentration is increased by itraconazole"), phenobarbital, phenytoin; antivirals: efavirenz, nevirapine.

Concomitant use of potent CYP3A4 inducers with itraconazole is not recommended. The above-mentioned drugs should not be initiated during treatment with itraconazole unless the potential benefit clearly outweighs the potential risk. The level of antifungal activity should be carefully monitored and the dose of itraconazole increased if necessary.

Drugs that increase itraconazole plasma concentrations

antibacterials: ciprofloxacin, clarithromycin, erythromycin; antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also below "Medicines whose plasma concentration is increased by itraconazole"), ritonavir (see also below "Medicines whose plasma concentration is increased by itraconazole").

These drugs should be used with caution when used concomitantly with itraconazole. Such patients should be carefully monitored for signs of increased or prolonged pharmacological effects of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor the concentration of itraconazole in the blood plasma.

Drugs whose plasma concentrations are increased by itraconazole

Itraconazole and its major metabolite hydroxy-itraconazole may inhibit the metabolism of drugs metabolized by CYP3A4 and the transport of drugs by P-glycoprotein, which may lead to an increase in the plasma concentrations of these drugs and/or their metabolites. Such an increase in plasma concentrations may lead to an increase or prolongation of the therapeutic effect and the occurrence of adverse reactions. Itraconazole and drugs metabolized by CYP3A4 that prolong the QT interval are contraindicated, as this may lead to the occurrence of ventricular tachyarrhythmias, including torsades de pointes with fatal outcome. After discontinuation of treatment, itraconazole is not detected in the blood plasma for a period of 7 to 14 days, depending on the dose and duration of treatment. In patients with cirrhosis of the liver or in patients who are simultaneously taking CYP3A4 inhibitors, drug withdrawal should be gradual. This is especially true for drugs whose metabolism is affected by itraconazole.

Drugs that interact with itraconazole are classified as "contraindicated", "not recommended", and "use with caution".

Contraindicated: under no circumstances should it be used simultaneously with itraconazole and within two weeks after stopping treatment with itraconazole.

Not recommended: The use of these drugs simultaneously and within 2 weeks after stopping itraconazole treatment should be avoided unless the benefit of treatment outweighs the potential risk of adverse reactions. If concomitant use cannot be avoided, such patients should be carefully monitored for signs of increased or prolonged pharmacological effect of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor the level of itraconazole concentration in the blood plasma.

Use with caution: Close monitoring is recommended when used concomitantly with itraconazole. Such patients should be carefully observed for signs of increased or prolonged pharmacological effects of itraconazole and the dose of itraconazole should be reduced if necessary. It is recommended to monitor itraconazole plasma concentrations.

Examples of drugs whose concentrations increase when co-administered with itraconazole are listed in Table 1 with corresponding recommendations for use.

Table 1

a See also “Drugs that decrease itraconazole plasma concentrations.”

b See also “Drugs that increase itraconazole plasma concentrations.”

Drugs that reduce the concentration of itraconazole

Concomitant use of itraconazole with the NSAID meloxicam reduces the concentration of the latter. Meloxicam should be used with caution simultaneously with itraconazole and the therapeutic or adverse effects should be monitored. It is recommended to adjust the dose of meloxicam.

Children

Drug interaction studies were conducted only in adult volunteers.

Application features

Cross-hypersensitivity

There is no evidence of cross-sensitivity between itraconazole and other azole antifungals. Caution should be exercised when prescribing itraconazole capsules to patients with hypersensitivity to other azoles.

Effect on the heart

In studies of itraconazole for injection in healthy volunteers, a transient, asymptomatic decrease in left ventricular ejection fraction was observed; it recovered before the next infusion. The clinical significance of these findings for the oral formulations is unknown.

Itraconazole is known to have a negative inotropic effect and cases of congestive heart failure have been reported in association with the drug. Spontaneous reports have shown a higher incidence of heart failure with a total daily dose of 400 mg than with lower daily doses, suggesting that the risk of heart failure may increase with the total daily dose of itraconazole.

The drug should not be used in patients with congestive heart failure or a history of this disease, except in cases where the expected benefit significantly outweighs the potential risk. When assessing the individual benefit/risk ratio, factors such as the severity of the indication, dosage regimen, duration of treatment (total daily dose) and individual risk factors for the development of congestive heart failure should be taken into account. These risk factors include the presence of heart disease, such as ischemic heart disease or valvular disease; severe lung disease, such as obstructive lung disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the symptoms of congestive heart failure, treatment should be carried out with caution, and symptoms of congestive heart failure should be monitored during treatment. If these symptoms appear during the course of treatment, the drug should be discontinued.

Calcium channel blockers may have a negative inotropic effect, which may potentiate the same effect of itraconazole. Itraconazole may also inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when itraconazole and calcium channel blockers are used simultaneously due to an increased risk of congestive heart failure (see section "Interaction with other medicinal products and other forms of interaction").

Severe hepatotoxicity, including acute fatal hepatic failure, has been reported very rarely with itraconazole capsules. Most of these cases have occurred in patients with a history of liver disease who were being treated for systemic indications, had other serious medical conditions, and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases occurred within the first month of treatment, including the first week. Therefore, it is advisable to monitor liver function in patients taking the drug. Patients should be advised to seek immediate medical attention if they develop symptoms of hepatitis, 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. In patients with elevated liver enzymes, active liver disease, or hepatotoxicity from other medications, treatment should only be initiated if the expected benefit outweighs the risk of liver damage. In such cases, liver enzyme monitoring is necessary.

Decreased stomach acidity

With reduced gastric acidity, the absorption of itraconazole from the capsules is impaired. Patients who simultaneously use drugs to reduce acidity (such as aluminum hydroxide) with Sporaxol should observe at least a 2-hour break between taking these drugs. Patients with achlorhydria, for example, AIDS patients or those taking H2 blockers or proton pump inhibitors, are recommended to take Sporaxol capsules with drinks such as cola.

Application to children.

Since there is insufficient clinical data on the use of itraconazole capsules in pediatric patients, itraconazole capsules should be prescribed to such patients only if the potential benefit significantly outweighs the potential risk.

Elderly patients

Due to limited clinical data on the use of itraconazole in elderly patients, the drug should be used in this category of patients if the expected benefit significantly outweighs the potential risks. Dosage for elderly patients is recommended to be selected taking into account the increased frequency of decreased liver, kidney or heart function, as well as concomitant diseases and treatment with other drugs.

Kidney dysfunction

There are limited data available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when administering the drug to this category of patients. The bioavailability of oral itraconazole may be reduced in patients with renal impairment. In such cases, dose adjustment may be considered.

Hearing loss

There have been reports of temporary or permanent hearing loss in patients taking itraconazole. In some cases, hearing loss occurred in the context of concomitant use with quinidine, which is contraindicated (see section "Interaction with other medicinal products and other forms of interaction"). Hearing usually recovers after discontinuation of Sporaxol therapy, but in some patients, hearing loss is irreversible.

Patients with immunodeficiency

In some patients with immunodeficiency (e.g. patients with neutropenia, AIDS or organ transplants), the oral bioavailability of Sporaxol may be reduced.

Patients with life-threatening systemic fungal infections

Due to its pharmacokinetic properties (see section "Pharmacokinetics"), Sporaxol capsules are not recommended for the primary treatment of emergency conditions caused by systemic fungal infections.

Patients with AIDS

For patients with AIDS who have been treated for a systemic fungal infection, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (meningeal or non-meningeal), and who are at risk of relapse, the physician should assess the need for maintenance treatment.

Neuropathy

If neuropathy occurs associated with the use of Sporaxol capsules, treatment should be discontinued.

Carbohydrate metabolism disorders

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

If, in the case of systemic candidiasis, it is suspected that the Candida species causing the disease are resistant to fluconazole, it cannot be assumed that they will be sensitive to itraconazole. Therefore, a sensitivity test should be performed before starting treatment with Sporaxol capsules.

Interaction potential

The use of itraconazole concomitantly with certain drugs may lead to changes in the effectiveness of itraconazole and/or the concomitant drugs, to life-threatening effects, and/or to sudden death.

Drugs contraindicated, not recommended, or recommended for use with caution concomitantly with itraconazole are listed in the section “Interaction with other medicinal products and other types of interactions”.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect on the reaction rate when driving vehicles or operating other mechanisms have not been conducted. It should be borne in mind that side effects such as dizziness, visual disturbances and hearing loss may occur (see section "Adverse reactions"), which may lead to negative consequences when driving vehicles and operating other mechanisms.

Use during pregnancy or breastfeeding

Pregnancy

Sporaxol should not be administered to pregnant women, except in cases of life-threatening systemic leukemias, when the potential benefit to the pregnant woman outweighs the risk of adverse effects on the fetus (see section "Contraindications").

Itraconazole has shown reproductive toxicity in animal studies.

There are limited data on the use of Sporaxol during pregnancy. During the post-marketing period, cases of developmental anomalies have been reported, including skeletal, genitourinary, cardiovascular and visual malformations, as well as chromosomal abnormalities and multiple malformations. A causal relationship to itraconazole use has not been established.

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

Women of reproductive age

Women of reproductive age taking Sporaxol capsules should use reliable contraception throughout the entire course of treatment until the first menstruation after its completion.

Breastfeeding period

Very small amounts of itraconazole are excreted in breast milk. Therefore, during breastfeeding, the potential risk to the child should be weighed against the expected benefit of treatment with Sporaxol for the mother. If treatment is necessary, the woman should stop breastfeeding.

Method of administration and doses

For oral use. For optimal absorption of the drug, Sporaxol capsules should be taken immediately after a meal. The capsules should be swallowed whole.

Table 2

Adult treatment regimens for each indication

The duration of treatment for systemic fungal infections is adjusted depending on the mycological and clinical response to therapy.

Table 3

Systemic mycoses

Since clinical data on the use of itraconazole capsules in elderly patients are limited, it is recommended to prescribe the drug to these patients only when the expected positive effect outweighs the possible risk.

Sporaxol should not be prescribed to elderly patients unless the expected benefit significantly outweighs the potential risks (see section "Special warnings and precautions for use").

Patients with renal impairment

Oral bioavailability of the drug may be reduced in patients with renal insufficiency; dose adjustment should be considered (see section "Special warnings and precautions for use").

Patients with liver dysfunction

Data on the use of oral itraconazole in patients with hepatic impairment are limited. The drug should be used with caution in such patients.

Children

Since clinical data on the use of itraconazole capsules in children are limited, Sporaxol should not be prescribed to children unless the expected benefit significantly outweighs the potential risks (see section "Special warnings and precautions for use").

Overdose

Symptoms: Overdose symptoms were similar to the adverse reactions observed when using the drug at recommended doses (see section "Adverse reactions").

Treatment. In case of accidental overdose, supportive measures should be taken. Activated charcoal may be administered if appropriate. Itraconazole is not removed by hemodialysis. There is no specific antidote.

Adverse reactions

The most common adverse reactions with itraconazole capsules in clinical trials and/or spontaneously reported were headache, abdominal pain and nausea. The most serious adverse reactions were severe allergic reactions, cardiac failure/congestive cardiac failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute hepatic failure) and severe skin reactions. For further information on other serious effects, see section 4.4.

Adverse reactions are grouped by system organ class and by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000).

Infections and infestations: uncommon – upper respiratory tract infections, sinusitis, rhinitis.

From the lymphatic system and blood: rarely - leukopenia.

Immune system disorders: uncommon – hypersensitivity*; rare – serum sickness; angioedema; anaphylactic reactions.

Metabolism: rarely - hypertriglyceridemia.

From the nervous system: often - headache; rarely - paresthesia, hypoesthesia, dysgeusia.

On the part of the organs of vision: rarely - visual disturbances, including blurred vision and diplopia.

From the side of the organs of hearing and vestibular apparatus: rarely - tinnitus, temporary or permanent hearing loss*.

Cardiac disorders: rarely – congestive heart failure*.

On the part of the respiratory system: rarely - dyspnea.

From the digestive system: often - abdominal pain, nausea; infrequently - vomiting, dyspepsia, diarrhea, constipation, bloating; rarely - pancreatitis.

Hepatobiliary system: infrequently - liver dysfunction; rarely - severe hepatotoxicity (including isolated cases of fatal acute liver failure)*, hyperbilirubinemia.

Skin and subcutaneous tissue disorders: infrequently - urticaria, rash, itching; rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity, alopecia.

From the urinary system: rarely - pollakiuria.

From the reproductive system and mammary glands: infrequently - menstrual disorders; rarely - erectile dysfunction.

General disorders: rarely - edema.

Laboratory tests: rarely - increased blood creatine phosphokinase levels.

*See section "Features of use".

The following adverse reactions associated with itraconazole have been additionally reported during clinical trials of itraconazole oral solution and/or intravenous solution.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia.

Immune system disorders: anaphylactoid reactions.

Metabolic: hyperglycemia, hyperkalemia, hypomagnesemia, hypokalemia.

On the part of the psyche: confusion of consciousness.

Nervous system disorders: drowsiness, peripheral neuropathy*, dizziness, tremor