VIZEALOT

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIZEALOT (VIZEALOT)

Composition:

Active substance: voriconazole;

1 vial contains 200 mg of voriconazole;

Excipients: hydroxypropylbetadex, sodium chloride, hydrochloric acid concentrated (for pH adjustment).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilized powder from white to almost white in color.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Voriconazole is a triazole antifungal agent. Its primary mechanism of action involves inhibition of the 14α-lanosterol demethylation reaction mediated by fungal cytochrome P450, a key step in ergosterol biosynthesis. Accumulation of 14α-methyl-sterols correlates with subsequent depletion of ergosterol in fungal cell membranes and may account for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P450 enzymes than for cytochrome P450 enzyme systems in various mammalian species.

Clinical efficacy and safety. In vitro, voriconazole demonstrates a broad spectrum of antifungal activity against Candida species (including the fluconazole-resistant species C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all tested Aspergillus species. In addition, voriconazole demonstrates in vitro fungicidal activity against emerging fungal pathogens, including Scedosporium and Fusarium species, which often exhibit limited susceptibility to existing antifungal agents.

Clinical efficacy (defined as partial or complete response) of voriconazole has been demonstrated against various Aspergillus species, including A. flavus, A. fumigatus, A. terreus, A. niger, and A. nidulans; various Candida species, including C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis; a limited number of strains of C. dubliniensis, C. inconspicua, and C. guilliermondii; various Scedosporium species, including S. apiospermum and S. prolificans; and various Fusarium species.

Other fungal infections against which voriconazole is effective (often with partial or complete response) include individual infections caused by various Alternaria species, Blastomyces dermatitidis, Blastoschizomyces capitatus, various Cladosporium species, Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, various Penicillium species (including P. marneffei), Phialophora richardsiae, Scopulariopsis brevicaulis, and various Trichosporon species, including infections caused by T. beigelii.

In vitro activity against clinical isolates has been observed for various Acremonium, Alternaria, Bipolaris, Cladophialophora, and Histoplasma capsulatum species, with inhibition of most strains occurring at voriconazole concentrations of 0.05–2 µg/mL.

In vitro activity of the drug has also been demonstrated against various Curvularia and Sporothrix species, although the clinical significance of this activity has not yet been established.

Control points. Prior to initiating therapy, fungal culture specimens and other appropriate laboratory tests (serological, histopathological) should be obtained to isolate and identify the causative pathogenic microorganisms. Therapy may be initiated before culture and laboratory results are available; however, once such results become available, etiological treatment should be adjusted accordingly.

Species most commonly causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei, for all of which the minimum inhibitory concentration (MIC) of voriconazole is less than 1 mg/L.

However, in vitro activity of voriconazole against different Candida species is not uniform. In particular, for C. glabrata, the MIC of voriconazole is proportionally higher in fluconazole-resistant strains compared to fluconazole-susceptible strains. Therefore, every effort should be made to identify Candida to the species level. If results of antifungal susceptibility testing of pathogens are available, MIC data may be interpreted using susceptibility breakpoint criteria established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1.

EUCAST Breakpoints

Pharmacokinetics.

General pharmacokinetic characteristics. Voriconazole pharmacokinetics have been studied in healthy volunteers, in specific populations, and in patients. When voriconazole was administered orally at doses of 200 mg or 300 mg twice daily for 14 days to patients at increased risk of developing aspergillosis (primarily patients with malignancies of lymphatic and hematopoietic tissues), the pharmacokinetic characteristics investigated—namely, rate and uniformity of absorption, accumulation, and nonlinear pharmacokinetics—were similar to those observed in healthy volunteers.

Voriconazole pharmacokinetics are nonlinear due to its extensive metabolism. With increasing dose, the increase in exposure is greater than proportional. It has been estimated that increasing the oral dose of voriconazole from 200 mg to 300 mg twice daily results in an average 2.5-fold increase in exposure (AUCτ). An oral loading dose of 200 mg (or 100 mg for patients with body weight below 40 kg) achieves exposure equivalent to 3 mg/kg administered intravenously. An oral loading dose of 300 mg (or 150 mg for patients with body weight below 40 kg) achieves exposure equivalent to 4 mg/kg administered intravenously. When loading doses of voriconazole are administered orally or intravenously, plasma concentrations approaching steady-state are achieved within the first 24 hours of therapy. If a loading dose regimen is not used, with repeated twice-daily administration, voriconazole accumulation and attainment of steady-state plasma concentrations typically occur by day 6 in most patients.

The safety of prolonged hydroxypropylbetadex exposure does not exceed 21 days (250 mg/kg/day).

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) occurring 1–2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is 96%. When voriconazole was administered repeatedly with a high-fat meal, Cmax and AUCτ decreased by 34% and 24%, respectively. Changes in gastric pH do not affect voriconazole absorption.

Distribution. The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, indicating extensive tissue distribution. Plasma protein binding of voriconazole is approximately 58%. Voriconazole has been detected in measurable quantities in cerebrospinal fluid samples from all 8 patients evaluated within a compassionate-use program.

Metabolism. In vitro studies have demonstrated that voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Voriconazole exhibits high inter-subject pharmacokinetic variability.

In vivo studies have shown that CYP2C19 plays a significant role in voriconazole metabolism. This enzyme exhibits genetic polymorphism. For example, it is expected that 15–20% of patients of Mongoloid race will be slow metabolizers of this drug. Among Caucasian and Negroid populations, the proportion of slow metabolizers is 3–5%. Studies conducted in healthy Caucasian and Japanese volunteers have demonstrated that in "slow metabolizers" of voriconazole, drug exposure (AUCτ) is on average 4 times higher than in the comparison group of homozygous "rapid metabolizers." Heterozygous "rapid metabolizers" have on average 2 times higher drug exposure than homozygous "rapid metabolizers."

The primary metabolite of voriconazole is the N-oxide, which accounts for 72% of the total radio-labeled metabolites circulating in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Excretion. Voriconazole is eliminated via hepatic metabolism; less than 2% of the administered dose is excreted unchanged in urine.

Following administration of radiolabeled voriconazole, approximately 80% of radioactivity was recovered in urine after multiple intravenous doses and 83% after multiple oral doses. The majority (>94%) of radioactive substances were eliminated within the first 96 hours after both intravenous and oral administration.

The elimination half-life of voriconazole is dose-dependent and is approximately 6 hours after an oral 200 mg dose. Due to nonlinear pharmacokinetics, the half-life is not used for assessing accumulation or elimination of voriconazole.

Pharmacokinetics in special patient populations.

Gender. Safety profiles and plasma concentrations of voriconazole in women and men were similar. Therefore, dose adjustment based on gender is not required.

Elderly patients. Safety profiles of voriconazole in younger and elderly patients were similar; thus, dose adjustment in elderly patients is not necessary (see section "Dosage and administration").

Pediatric patients. This patient population demonstrated greater individual variability compared to adults.

Comparison of pharmacokinetic parameters between pediatric and adult patients showed that the expected total exposure (AUCτ) in children after an intravenous loading dose of 9 mg/kg was comparable to AUCτ in adults after an intravenous loading dose of 6 mg/kg. AUCτ in children after intravenous maintenance doses of 4 and 8 mg/kg twice daily was comparable to AUCτ in adults receiving 3 and 4 mg/kg twice daily intravenously. AUCτ in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults receiving 200 mg orally twice daily. Exposure after an intravenous dose of 8 mg/kg will be twice higher than after an oral dose of 9 mg/kg.

The higher intravenous maintenance dose in children compared to adults reflects greater elimination capacity due to a higher liver mass relative to body weight. Oral bioavailability of voriconazole may be reduced in children with malabsorption or very low body weight for age. In such cases, intravenous voriconazole is recommended.

Exposure to voriconazole in most older children was comparable to that in adults when the same dosing regimen was used. However, in some older children with low body weight, lower voriconazole exposure was observed compared to adults. It appears that in such patients, voriconazole metabolism occurs via a pathway similar to that in children rather than in adults. Based on population pharmacokinetic analysis, adolescents aged 12–14 years with body weight less than 50 kg should receive pediatric dosing (see section "Dosage and administration").

Renal impairment. In a study administering a single 200 mg dose to patients with normal renal function, mild renal impairment (creatinine clearance 41–60 mL/min), and severe renal impairment (creatinine clearance <20 mL/min), the severity of renal dysfunction had minimal effect on voriconazole pharmacokinetics. Plasma protein binding of voriconazole was similar across patients with varying degrees of renal impairment (see sections "Dosage and administration" and "Special precautions").

In patients with normal renal function, the pharmacokinetic profile of hydroxypropylbetadex in voriconazole 200 mg powder for solution for infusion is characterized by a short elimination half-life of 1–2 hours and does not demonstrate accumulation with consecutive daily doses. In healthy subjects and patients with mild to severe renal impairment, more than 85% of an 8 g dose of hydroxypropylbetadex is excreted in urine. In patients with mild, moderate, and severe renal impairment, elimination half-lives increased approximately 2-, 4-, and 6-fold, respectively, compared to normal. In these patients, consecutive infusions may lead to accumulation of hydroxypropylbetadex until a steady state is reached. The clearance of hydroxypropylbetadex during hemodialysis is 37.5 ± 24 mL/min.

Hepatic impairment. After a single oral dose of voriconazole (200 mg) in patients with mild or moderate hepatic cirrhosis (Child-Pugh class A and B), AUCτ was 233% higher than in patients with normal hepatic function. Hepatic impairment does not affect voriconazole plasma protein binding.

In a clinical study of repeated oral voriconazole administration, AUCτ was similar in patients with moderate hepatic cirrhosis (Child-Pugh class B) receiving a maintenance dose of 100 mg twice daily and in patients with normal hepatic function receiving 200 mg twice daily. Pharmacokinetic data in patients with severe hepatic cirrhosis (Child-Pugh class C) are lacking (see sections "Dosage and administration" and "Special precautions").

Clinical characteristics.

Indications.

Prophylaxis of invasive fungal infections in patients undergoing allogeneic bone marrow transplantation who are at high risk of such complications.

Voriconazole should be used in adults and children for the treatment of:

• invasive aspergillosis;
• candidemia in non-neutropenic patients;
• severe invasive infections caused by Candida species (including Candida krusei) resistant to fluconazole;
• severe fungal infections caused by Scedosporium and Fusarium species.

Visealot should be used as initial therapy in patients with progressive or potentially life-threatening infections.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, or ivabradine, as increased plasma concentrations of these medicinal products may lead to QTc interval prolongation and, rarely, to the development of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with rifampicin, carbamazepine, and phenobarbital, as these medicinal products can significantly reduce voriconazole plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of standard doses of voriconazole with efavirenz at doses of 400 mg per day or higher, as efavirenz at these doses significantly reduces voriconazole plasma concentrations in healthy volunteers. Voriconazole also significantly increases efavirenz plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"; for use of lower doses, see section "Special precautions").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily), as such ritonavir doses lead to a significant reduction in voriconazole plasma concentration in healthy volunteers (for use of lower ritonavir doses, see section "Special precautions").
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as increased plasma concentrations of these medicinal products may lead to ergotism (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with St. John's wort (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with venetoclax at the initiation of venetoclax treatment and during the dose-titration phase, as voriconazole is likely to significantly increase venetoclax plasma concentration and increase the risk of tumor lysis syndrome (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Voriconazole inhibits and is metabolized by cytochrome P450 isoenzymes: CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole has the potential to increase plasma concentrations of substances metabolized by these cytochrome P450 isoenzymes, particularly those metabolized by CYP3A4, as voriconazole is a strong inhibitor of CYP3A4, although the extent of AUC increase depends on the substrate (see table below).

Drug interaction studies were conducted in healthy male volunteers who received oral voriconazole 200 mg twice daily repeatedly until steady state was achieved. The results obtained are also applicable to other patient groups and routes of administration.

Voriconazole should be used with caution in patients who are concurrently taking other medicinal products that prolong the QTc interval. In cases where voriconazole also has the potential to increase plasma concentrations of substances metabolized by CYP3A4 isoenzymes (e.g., certain antihistamines, quinidine, cisapride, pimozide, and ivabradine), their concomitant use is contraindicated.

Information on interactions between voriconazole and other medicinal products is presented in Table 2. The direction of arrows for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio.

Symbols and abbreviations used in the table and their meanings: ↔ — within 80–125%; ↑ — above 80–125%; ↓ — below 80–125%; * — bidirectional interaction; AUCτ — area under the curve over the dosing interval; AUCt — area under the curve from time "0" to a defined time point; AUC0–∞ — area under the curve from time "0" to infinity; n/a — not applicable.

Interactions in the table are listed in the following order:

concomitant use contraindicated;

concomitant use requires dose adjustment and careful clinical and biological monitoring;

concomitant use does not cause significant pharmacokinetic interactions but may be of clinical interest.

Table 2.

Special precautions for use.

Hypersensitivity. Voriconazole should be used with caution in patients with hypersensitivity to other azoles (see section "Adverse reactions").

Duration of use. Vizealot should not be administered intravenously for longer than 6 months.

Cardiovascular system. Voriconazole is associated with QTc interval prolongation. Cases of torsades de pointes ventricular tachycardia have been rarely observed in patients with risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant use of medicinal products that may predispose to this condition. Voriconazole should be used with caution in patients with potentially proarrhythmic conditions, such as:

• congenital or acquired QTc interval prolongation;
• cardiomyopathy, especially in the presence of heart failure;
• sinus bradycardia;
• presence of symptomatic arrhythmias;
• concomitant use of medicinal products that may prolong the QTc interval.

Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and corrected if necessary before initiating and during treatment with voriconazole (see section "Posology and method of administration"). A study in healthy volunteers assessed the effect of single doses of voriconazole up to 4 times the standard daily dose on the QTc interval. In no study participant did the duration of this interval exceed the potentially clinically significant threshold of 500 ms (see section "Pharmacodynamics").

Infusion-related reactions. Infusion-related reactions have been observed during administration of the medicinal product, primarily flushing and nausea. Depending on the severity of symptoms, discontinuation of therapy should be considered (see section "Adverse reactions").

Hepatotoxicity. During clinical trials, serious hepatic reactions (including clinically apparent hepatitis, cholestasis, and fulminant hepatic failure, including fatal cases) have been observed with voriconazole. Hepatic reactions occurred primarily in patients with severe underlying conditions (especially hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, have been observed in patients without other identified risk factors. Liver function abnormalities were reversible and usually normalized after discontinuation of therapy (see section "Adverse reactions").

Liver function monitoring. Patients receiving voriconazole should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (including aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels) at the start of Vizealot treatment and at least once weekly during the first month of treatment. The duration of treatment should be as short as possible; however, if treatment continues based on benefit-risk assessment (see section "Posology and method of administration"), the frequency of monitoring may be reduced to once monthly provided there are no changes in liver function tests.

If liver function tests show significant elevation, Vizealot should be discontinued, except when medical evaluation of the benefit-risk ratio justifies continued use of the medicinal product.

Liver function monitoring should be performed in both children and adults.

Serious cutaneous adverse reactions.

• Photosensitivity. Use of the medicinal product Vizealot has additionally been associated with photosensitivity reactions such as freckles, lentigines, actinic keratosis, and pseudoporphyria. All patients, including children, should avoid direct sunlight exposure, wear protective clothing, and use sunscreen with a high protection factor (SPF) during treatment.
• Squamous cell carcinoma of the skin. Among patients in whom squamous cell carcinoma (SCC) of the skin (including SCC in situ or Bowen's disease) was documented, there were patients who previously experienced photosensitivity reactions. In case of photosensitivity reactions, multidisciplinary consultations should be conducted, treatment with Vizealot should be discontinued, and alternative antifungal agents should be considered, with referral to a dermatologist. If treatment with Vizealot continues, a dermatologist should systematically and regularly examine the patient for early detection and treatment of potential precancerous lesions. If precancerous skin lesions or squamous cell carcinoma are detected, treatment with Vizealot must be discontinued (see below "Long-term treatment").
• Serious skin reactions. Serious cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during voriconazole use. Patients presenting with rash should be closely monitored, and use of Vizealot should be discontinued if signs of disease progression occur.

Adrenal gland effects

Adrenal insufficiency has occurred in some patients due to use of other azoles (e.g., ketoconazole).

Reversible cases of adrenal insufficiency have been observed in patients receiving voriconazole.

Patients undergoing long-term treatment with voriconazole and corticosteroids (including inhaled, e.g., budesonide, and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during and after treatment with voriconazole (see section "Interaction with other medicinal products and other forms of interaction").

Long-term treatment. Long-term use of the medicinal product (for treatment or prophylaxis) beyond 180 days (6 months) requires careful benefit-risk assessment. Additionally, physicians should consider reducing the dose of Vizealot (see sections "Posology and method of administration" and "Pharmacodynamics").

Cases of squamous cell carcinoma of the skin (including SCC in situ or Bowen's disease) have been reported in association with long-term use of voriconazole.

In patients who have undergone transplant surgery, non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed. If a patient develops skeletal pain and radiological signs indicate periostitis, multidisciplinary consultations should be conducted and discontinuation of Vizealot should be considered.

Ocular adverse reactions. Prolonged adverse reactions affecting vision, including blurred vision, optic neuritis, and optic disc edema, have been reported (see section "Adverse reactions").

Renal adverse reactions. Acute renal failure has been reported with voriconazole use in patients with severe underlying conditions. Decreased renal function may occur in patients receiving voriconazole concomitantly with nephrotoxic medicinal products and/or underlying conditions (see section "Adverse reactions").

Renal function monitoring. Patients should be monitored for possible renal function impairment. Monitoring should include assessment of laboratory parameters, particularly serum creatinine levels.

Pancreatic function monitoring. Careful monitoring of patients, especially children, with risk factors for acute pancreatitis such as recent chemotherapy or hematopoietic stem cell transplantation, should be conducted during treatment. Monitoring of serum amylase or lipase levels may be necessary.

Children. Safety and efficacy of Vizealot in children under 2 years of age have not been established (see sections "Adverse reactions" and "Pharmacodynamics"). Voriconazole is recommended for use in children aged 2 years and older. Increased liver enzyme levels have been observed more frequently in children (see section "Adverse reactions"). Liver function monitoring is required for both adults and children. In patients aged 2 to 12 years, oral bioavailability of voriconazole may be limited due to malabsorption and very low body weight. Intravenous voriconazole is recommended for these patients.

• Serious cutaneous adverse reactions (including squamous cell carcinoma of the skin). The incidence of photosensitivity reactions is higher in children. If skin lesions progress toward squamous cell carcinoma in this patient group, intensified measures for sun protection should be implemented. Children with signs of photoaging, such as freckles or lentigines, should be monitored by a dermatologist and avoid sun exposure even after discontinuation of the medicinal product.

Prevention. In case of treatment-related adverse reactions (hepatotoxicity, severe skin reactions including photosensitivity and squamous cell carcinoma, severe or prolonged visual disturbances, and periostitis), discontinuation of voriconazole and use of alternative antifungal agents should be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer). When phenytoin and voriconazole are used concomitantly, careful monitoring of plasma phenytoin levels is recommended. Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk (see section "Interaction with other medicinal products and other forms of interaction").

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate). When voriconazole and efavirenz are used concomitantly, the voriconazole dose should be increased to 400 mg every 12 hours and the efavirenz dose reduced to 300 mg every 24 hours (see sections "Posology and method of administration", "Contraindications", and "Interaction with other medicinal products and other forms of interaction").

Rifabutin (potent CYP450 inducer). When voriconazole and rifabutin are used concomitantly, careful monitoring of complete blood count and rifabutin-related adverse reactions (such as uveitis) is required. Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk (see section "Interaction with other medicinal products and other forms of interaction").

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate). Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless benefit to the patient from voriconazole use outweighs the risk (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Everolimus (CYP3A4 substrate, P-glycoprotein substrate). Concomitant use of everolimus and voriconazole is not recommended, as voriconazole is expected to cause a significant increase in everolimus concentration. Currently, there is insufficient information on dosage regimen (see section "Interaction with other medicinal products and other forms of interaction").

Naloxegol (CYP3A4 substrate). Concomitant use of voriconazole and naloxegol is not recommended, as voriconazole is expected to significantly increase naloxegol concentrations. Currently, there is insufficient data to provide clear dosing recommendations for naloxegol in this situation (see section "Interaction with other medicinal products and other forms of interaction").

Methadone (CYP3A4 substrate). When methadone and voriconazole are used concomitantly, careful monitoring for development of methadone-related adverse reactions and toxicity (including QTc interval prolongation) is recommended, as methadone levels increase with concomitant voriconazole use. Dose reduction of methadone may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Short-acting opioids (CYP3A4 substrates). When short-acting opioids and voriconazole are used concomitantly, dose reduction of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil) should be considered (see section "Interaction with other medicinal products and other forms of interaction"). Careful monitoring of opioid-related adverse reactions (including prolonged monitoring of respiratory function) may be necessary, as the half-life of alfentanil is prolonged 4-fold with concomitant voriconazole use, and according to independently published study data, concomitant use of fentanyl and voriconazole increased the mean AUC0–∞ of fentanyl.

Long-acting opioids (CYP3A4 substrates). When long-acting opioids and voriconazole are used concomitantly, dose reduction of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone) should be considered. Careful monitoring of opioid-related adverse reactions may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Fluconazole (CYP2C9, CYP2C19, and CYP3A4 inhibitor). Concomitant oral administration of voriconazole and fluconazole results in significant increases in Cmax and AUCτ of voriconazole in healthy volunteers. It is unknown what dose reduction and/or dosing frequency adjustment of voriconazole and fluconazole would prevent this effect. Monitoring for voriconazole-related adverse reactions is recommended when voriconazole is used immediately after fluconazole (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Sodium. Each vial of the medicinal product Vizealot contains 88.75 mg of sodium, which should be considered when administering the product to patients who need to control sodium intake.

Cyclodextrins. The powder for solution for infusion contains cyclodextrins (2400 mg cyclodextrins per vial, equivalent to 120 mg/mL when 20 mL of ready-to-use solution is prepared). This may affect the properties (e.g., toxicity) of the active substance and other medicinal products. The safety aspects of cyclodextrins were studied during the development and safety evaluation of the medicinal product.

Since cyclodextrins are eliminated via the kidneys, accumulation of cyclodextrin may occur in patients with moderate or severe renal dysfunction.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of Vizealot in pregnant women.

Animal studies have demonstrated reproductive toxicity. The potential risk for humans is unknown.

Vizealot should not be used during pregnancy except when the benefit to the mother clearly outweighs the potential risk to the fetus.

Women of childbearing potential who may become pregnant should use effective contraception during treatment with the medicinal product.

Breastfeeding. Excretion of voriconazole into breast milk has not been studied; therefore, breastfeeding should be discontinued during treatment with Vizealot.

Fertility. Animal studies did not demonstrate impaired fertility in animals.

Ability to drive and use machines.

Vizealot has a moderate influence on the ability to drive and use machinery. The medicinal product may cause reversible visual disturbances, including blurred vision, altered/enhanced visual perception, and/or photophobia. Patients experiencing such symptoms should avoid potentially hazardous activities such as driving or operating machinery.

Method of administration and dosage.

Before initiating treatment with the medicinal product Visealot and during its administration, monitoring of electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be performed, and correction should be carried out if necessary (see section "Special precautions"). The medicinal product Visealot is intended only for intravenous infusion.

Visealot should be administered at a maximum rate of 3 mg/kg/hour over 1–3 hours.

Treatment.

Adults. To achieve plasma concentrations close to steady-state levels on the first day, treatment with Visealot should be initiated using an appropriate regimen of loading doses, either intravenously or orally. Due to the high bioavailability of voriconazole after oral administration (96%), the route of administration may be switched from intravenous to oral and vice versa, depending on clinical indications. Detailed dosing recommendations are provided in Table 3.

Table 3.

* Including patients aged 15 years and older.

Duration of treatment. Treatment duration should be as short as possible, depending on the patient's clinical and mycological response. If treatment with the drug is required for more than 180 days (6 months), a careful benefit-risk assessment should be performed (see sections "Special precautions" and "Pharmacodynamics").

Dose adjustment in adults. If patients are unable to tolerate intravenous administration of the drug at a dose of 4 mg/kg twice daily, the dose should be reduced to 3 mg/kg twice daily.

If an adequate response to treatment is not observed, the maintenance dose may be increased to 300 mg orally twice daily. For patients with body weight less than 40 kg, the voriconazole dose may be increased to 150 mg orally twice daily.

For patients intolerant to higher doses of voriconazole, the dose should be gradually reduced by 50 mg until reaching a maintenance dose of 200 mg twice daily orally (or 100 mg twice daily orally for patients with body weight less than 40 kg).

If treatment-related adverse reactions occur, discontinuation of voriconazole and initiation of alternative antifungal agents should be considered (see sections "Adverse reactions" and "Pharmacodynamics").

Dose adjustment when co-administered with other agents. Rifabutin or phenytoin may be co-administered with voriconazole provided that the maintenance dose of voriconazole is increased to 5 mg/kg twice daily intravenously (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). Efavirenz may be co-administered with voriconazole provided that the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the dose of efavirenz is reduced by 50%, i.e., to 300 mg once daily. After discontinuation of voriconazole, the initial dose of efavirenz should be resumed (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Elderly patients. Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Renal impairment. In patients with moderate to severe renal impairment (creatinine clearance < 50 ml/min), accumulation of sodium hydroxypropylbetadex occurs. Oral formulations of voriconazole should be used in these patients, except when the benefit of intravenous voriconazole outweighs the risks. In such cases, careful monitoring of serum creatinine levels is required. If serum creatinine increases, switching from intravenous to oral voriconazole should be considered (see section "Pharmacokinetics"). Voriconazole clearance during hemodialysis is 121 ml/min. The amount of voriconazole removed during a 4-hour hemodialysis session is negligible; therefore, dose adjustment is not necessary.

The clearance of hydroxypropylbetadex during hemodialysis is 37.5 ± 24 ml/min.

Hepatic impairment. For patients with mild to moderate hepatic cirrhosis (Child-Pugh class A or B), standard loading dose regimens are recommended, while the maintenance dose should be halved (see section "Pharmacokinetics").

Studies on the use of Visealot in patients with severe chronic hepatic cirrhosis (Child-Pugh class C) have not been conducted.

Information on the safety of voriconazole in patients with abnormal liver function test results (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin levels more than 5 times the upper limit of normal) is limited.

Use of Visealot has been associated with elevated liver function tests and clinical signs of liver injury, such as jaundice; therefore, the drug should be used in patients with severe hepatic impairment only if the benefit outweighs the potential risk. Close monitoring of patients with hepatic impairment for development of drug-related toxic effects is required (see section "Adverse reactions").

Method of administration. Prior to intravenous infusion, the drug must be reconstituted and diluted. Visealot is not intended for bolus injection.

To obtain 20 ml of a clear concentrate containing 10 mg/ml voriconazole, the powder should be dissolved in 19 ml of water for injections or in 19 ml of 9 mg/ml (0.9%) sodium chloride infusion solution. Do not use the Visealot vial if the diluent does not get drawn into the vial by vacuum force. A standard (non-automatic) 20 ml syringe is recommended to ensure accurate addition of 19 ml of water for injections or 9 mg/ml (0.9%) sodium chloride infusion solution. The medicinal product is intended for single use only; only clear solutions free from mechanical particles should be used.

To obtain an infusion-ready solution, i.e., a voriconazole solution with a concentration of 0.5–5 mg/ml, the required volume of the reconstituted concentrate should be added to a compatible recommended infusion solution (detailed information provided below).

Table 4.

Required volumes of Visealot concentrate (10 mg/ml)

The reconstituted solution may be diluted as follows:

• 9 mg/mL (0.9%) sodium chloride solution for injection;
• compound sodium lactate solution for intravenous infusion;
• 5% glucose and lactated Ringer's solution for intravenous infusion;
• 5% glucose and 0.45% sodium chloride solution for intravenous infusion;
• 5% glucose solution for intravenous infusion;
• 5% glucose solution with 20 mEq potassium chloride for intravenous infusion;
• 0.45% sodium chloride solution for intravenous infusion;
• 5% glucose and 0.9% sodium chloride solution for intravenous infusion.

Compatibility of voriconazole with other solvents is unknown.

Any unused solution should be disposed of according to local requirements. Information on the use of the medicinal product for prophylaxis is provided below.

Prophylaxis in adults and children. Prophylaxis should be initiated on the day of transplantation; its duration may extend up to 100 days. Prophylaxis should be as short as possible, depending on the risk of developing invasive fungal infections determined by signs of neutropenia or immunosuppression. Extending prophylaxis up to 180 days after transplantation may be considered only in cases of ongoing immunosuppression or graft-versus-host disease.

Dosing. The recommended dosing regimen for prophylaxis is the same as for treatment in the corresponding age groups (see Tables 3 and 5).

Duration of prophylaxis. The safety and efficacy of using voriconazole for longer than 180 days have not been adequately studied in clinical trials. Use of voriconazole as prophylaxis for longer than 180 days (6 months) requires careful assessment of the benefit-risk ratio.

The information below applies to both treatment and prophylaxis.

Dose adjustment. Dose adjustment due to lack of efficacy or development of treatment-related adverse reactions is not recommended when the medicinal product is used for prophylaxis.

Children.

The medicinal product can be used in children from 2 years of age. Safety and efficacy of Vizealot in children under 2 years of age have not been established.

Information on the use of the medicinal product for prophylaxis in children is provided above.

Children aged 2–12 years and children aged 12–14 years with body weight < 50 kg.

The following treatment regimen is recommended:

Table 5.

It is recommended to initiate therapy with intravenous administration, and oral formulations of voriconazole should be considered only after significant clinical improvement has been achieved. It should be noted that an intravenous dose of 8 mg/kg provides voriconazole exposure approximately twice that achieved with an oral dose of 9 mg/kg.

For pediatric patients aged 12–14 years with body weight ≥ 50 kg and patients aged 15–17 years regardless of body weight, the same voriconazole doses as in adults should be administered.

Dose adjustment for pediatric patients aged 2–12 years and patients aged 12–14 years with body weight < 50 kg. If the patient's response to treatment is inadequate, the intravenous dose may be increased by 1 mg/kg increments. If the patient does not tolerate treatment, the intravenous dose of Visealot must be reduced by 1 mg/kg decrements. The use of the drug in pediatric patients aged 2–12 years with renal or hepatic impairment has not been studied (see sections "Side Effects" and "Pharmacokinetics").

Overdose.

During clinical trials, three cases of accidental overdose were reported. All three cases occurred in children who received intravenous doses up to five times higher than the recommended dose. The only adverse reaction reported was photophobia lasting 10 minutes. There is no known antidote for voriconazole.

The clearance of voriconazole during hemodialysis is 121 ml/min. The clearance of hydroxypropylbetadex during hemodialysis is 37.5 ± 24 ml/min. In cases of overdose, hemodialysis may enhance the elimination of voriconazole and hydroxypropylbetadex from the body.

Adverse Reactions

The most commonly reported adverse reactions included visual disturbances, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, abnormal liver function tests, respiratory disorders, and abdominal pain.

Overall, adverse reactions were mild to moderate in severity. Analysis of safety data did not reveal any clinically significant differences based on age, race, or gender.

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Common: sinusitis
Uncommon: pseudomembranous colitis

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Frequency not known: squamous cell carcinoma (including cutaneous squamous cell carcinoma in situ or Bowen’s disease)*.

Blood and lymphatic system disorders

Common: agranulocytosis\1, pancytopenia, thrombocytopenia\2, leucopenia, anaemia
Uncommon: bone marrow failure, lymphadenopathy, eosinophilia
Rare: disseminated intravascular coagulation syndrome

Immune system disorders

Uncommon: hypersensitivity
Rare: anaphylactoid reactions

Endocrine disorders

Uncommon: adrenal insufficiency, hypothyroidism
Rare: hyperthyroidism

Metabolism and nutrition disorders

Very common: peripheral oedema
Common: hypoglycaemia, hypokalaemia, hyponatraemia

Psychiatric disorders

Common: depression, hallucinations, anxiety, insomnia, agitation, confusion

Nervous system disorders

Very common: headache
Common: seizures, syncope, tremor, hypertension\3, paraesthesia, somnolence, dizziness
Uncommon: cerebral oedema, encephalopathy\4, extrapyramidal disorders\5, peripheral neuropathy, ataxia, hypaesthesia, dysgeusia
Rare: hepatic encephalopathy, Guillain-Barré syndrome, nystagmus

Eye disorders

Very common: visual disturbances\6
Common: retinal haemorrhage
Uncommon: optic nerve disorders\7, optic disc oedema\8, ocular hypertensive crisis, diplopia, scleritis, blepharitis
Rare: optic nerve atrophy, corneal clouding

Ear and labyrinth disorders

Uncommon: hearing impairment, vertigo, tinnitus

Cardiac disorders

Common: supraventricular arrhythmia, tachycardia, bradycardia
Uncommon: ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, QT interval prolongation on electrocardiogram, supraventricular tachycardia
Rare: torsades de pointes, complete atrioventricular block, bundle branch block, nodal rhythm

Vascular disorders

Common: arterial hypotension, phlebitis
Uncommon: thrombophlebitis, lymphangitis

Respiratory, thoracic and mediastinal disorders

Very common: dyspnoea\9
Common: acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal disorders

Very common: diarrhoea, vomiting, abdominal pain, nausea
Common: cheilitis, dyspepsia, constipation, gingivitis
Uncommon: peritonitis, pancreatitis, tongue oedema, duodenitis, gastroenteritis, glossitis

Hepatobiliary disorders

Very common: abnormal liver function tests
Common: jaundice, cholestatic jaundice, hepatitis\10
Uncommon: hepatic failure, hepatomegaly, cholecystitis, cholelithiasis

Skin and subcutaneous tissue disorders

Very common: rash
Common: exfoliative dermatitis, alopecia, maculopapular rash, pruritus, erythema
Uncommon: Stevens-Johnson syndrome, photosensitivity, purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema
Rare: toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)\8, angioneurotic oedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, toxidermia
Frequency not known: cutaneous lupus erythematosus*, freckles*, lentigo*

Musculoskeletal and connective tissue disorders

Common: back pain
Uncommon: arthritis
Frequency not known: periostitis*

Renal and urinary disorders

Common: acute renal failure, haematuria
Uncommon: renal tubular necrosis, proteinuria, nephritis

General disorders and administration site conditions

Very common: pyrexia
Common: chest pain, facial oedema\11, asthenia, chills
Uncommon: infusion site reaction, influenza-like illness

Investigations

Common: increased blood creatinine
Uncommon: increased blood urea, increased blood cholesterol

* Adverse reactions identified post-marketing.

1 Including febrile neutropenia and neutropenia.
2 Including immune thrombocytopenic purpura.
3 Including nuchal rigidity and tetany.
4 Including hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
5 Including akathisia and parkinsonism.
6 See subsection "Visual disturbances" below.
7 Post-marketing reports of prolonged optic neuritis (see section "Special warnings and precautions for use").
8 See section "Special warnings and precautions for use".
9 Including dyspnoea and exertional dyspnoea.
10 Including drug-induced liver injury, toxic hepatitis, hepatocellular injury, and hepatotoxicity.
11 Including periorbital oedema, lip oedema, and mouth oedema.

Visual disturbances. During clinical and therapeutic studies, visual disturbances (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, ocular disorders, halos around lights, night blindness, oscillopsia, photopsia, flickering scotoma, decreased visual acuity, visual brightness, visual field defect, floaters, and xanthopsia) were very commonly observed with voriconazole use. These visual disturbances were transient and resolved spontaneously in most cases within 60 minutes; no clinically significant long-term visual effects were observed. Symptoms tended to diminish with repeated dosing. Visual disturbances were generally mild, rarely led to drug discontinuation, and were not associated with prolonged irreversible effects. Visual disturbances may be related to high plasma concentrations and/or drug doses.

The mechanism of visual disturbances is unknown, although the drug likely affects the retina. Voriconazole administration caused a reduction in the amplitude of waves on electroretinogram during a clinical study assessing the effect of voriconazole on retinal function in healthy volunteers. Changes on electroretinogram did not progress over 29 days of therapy and fully resolved after voriconazole discontinuation.

Post-marketing, prolonged ocular adverse reactions have been reported (see section "Special warnings and precautions for use").

Skin reactions. Skin reactions were very commonly observed in patients receiving voriconazole in clinical trials; however, these patients were also receiving multiple other medications for treatment of severe underlying conditions. Most rashes were mild or moderate in severity. Serious skin reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (rare), and erythema multiforme (rare), occurred during voriconazole use (see section "Special warnings and precautions for use").

Patients developing rashes should be closely monitored, and if lesions progress, treatment with Vizealot should be discontinued.

Rare cases of serious photosensitivity reactions, including freckles, lentigo, and actinic keratosis, have been reported, particularly during long-term treatment (see section "Special warnings and precautions for use").

Cases of squamous cell carcinoma (including cutaneous squamous cell carcinoma in situ or Bowen’s disease) have been reported in patients receiving long-term voriconazole; the mechanism of this phenomenon is not established (see section "Special warnings and precautions for use").

Liver function tests. During clinical trials, the overall incidence of transaminase elevations > 3 times the upper limit of normal (not necessarily considered an adverse reaction) was 18.0% (319/1768) in adults and 25.8% (73/283) in children receiving voriconazole for treatment and prophylaxis. Abnormal liver function tests may be associated with high plasma concentrations and/or drug doses. Most abnormalities resolved during continued treatment without dose adjustment or after dose modification, including drug discontinuation.

In patients with other severe underlying conditions, voriconazole use has been associated with serious hepatotoxic reactions, including jaundice, hepatitis, and fatal hepatic failure (see section "Special warnings and precautions for use").

Infusion-related reactions. Anaphylactoid-type reactions, including flushing, hot flushes, increased sweating, tachycardia, chest tightness, dyspnoea, syncope, nausea, pruritus, and rash, have been reported. Symptoms occurred immediately after the start of infusion (see section "Special warnings and precautions for use").

Prophylaxis. In a study comparing voriconazole and itraconazole for primary prophylaxis in adult and adolescent recipients of allogeneic haematopoietic stem cell transplantation without prior confirmed or suspected invasive fungal infection, final discontinuation due to adverse reactions occurred in 39.3% of patients receiving voriconazole compared to 39.6% in the itraconazole group. Treatment-related hepatic adverse reactions led to final discontinuation in 21.4% of patients receiving voriconazole and 7.1% receiving itraconazole.

Paediatric population. The safety of voriconazole was evaluated in children aged 2–12 years and 12–18 years receiving voriconazole for prophylaxis and treatment in clinical trials. Safety was also assessed in children aged 2–12 years in compassionate-use programs. Overall, the safety profile in children was similar to that in adults. However, a higher tendency for elevation of liver enzymes was observed in children compared to adults, reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the frequency of skin reactions (particularly erythema) may be slightly higher in children than in adults. In patients under 2 years of age receiving voriconazole in compassionate-use programs, adverse reactions with a possible causal relationship to voriconazole included photosensitivity reactions, arrhythmia, pancreatitis, increased blood bilirubin, elevated liver enzymes, rash, and optic disc oedema. Pancreatitis has also been reported in children during post-marketing use.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years from the date of manufacture of in bulk.

Storage conditions.

Store out of reach of children at a temperature not exceeding 25 °C.

Detailed storage recommendations for the medicinal product.

From a microbiological standpoint, the medicinal product should be used immediately after reconstitution. If not used immediately, the user is responsible for storage conditions and duration prior to use; normally, storage should not exceed 24 hours at 2–8 °C (refrigerated), unless reconstitution was performed under controlled and validated aseptic conditions. Physical and chemical stability of the solution has been demonstrated for 72 hours at 15–25 °C (room temperature) and at 2–8 °C (refrigerated).

Incompatibilities.

Infusion of Vizealot must not be administered simultaneously with other intravenous medicinal products using the same infusion line or cannula. The line must be flushed to ensure completion of infusion. After completion of Vizealot infusion, the same line may be used for administration of other intravenous medicinal products.

Blood products and short-term infusions of concentrated electrolyte solutions: Electrolyte imbalances such as hypokalaemia, hypomagnesaemia, and hypocalcaemia should be corrected prior to initiation of voriconazole therapy (see sections "Dosage and administration" and "Special warnings and precautions for use"). Vizealot must not be administered simultaneously with any blood product or any short-term infusion of concentrated electrolyte solutions, even if both infusions are administered through separate lines. Total parenteral nutrition (TPN): TPN should not be discontinued during Vizealot administration but must be administered through a separate line. When using a multi-lumen catheter for TPN, a separate port should be used, not the port used for Vizealot infusion. Vizealot must not be reconstituted with 4.2% sodium bicarbonate infusion solution. Compatibility with this solution at other concentrations is unknown. This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

1 vial of powder for infusion solution per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

(Manufactured from in bulk by Anfarm Hellas S.A., Greece).

Manufacturer's location and address of place of business.

Ukraine, 18030, Cherkasy Oblast, Cherkasy, Kobzarska St., 108. Tel.: (044) 281-01-01.