Vizol

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

Composition:

Active substance: voriconazole;

1 vial contains 200 mg of voriconazole;

Excipients: hydroxypropyl betadex; lactose monohydrate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: lyophilized powder of white to almost white 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-methylsterol 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 mammals.

Pharmacokinetics/pharmacodynamics. Across 10 therapeutic studies, the median average and maximum plasma concentrations for each individual patient were 2425 ng/mL (interquartile range 1193–4380 ng/mL) and 3742 ng/mL (interquartile range 2027–6302 ng/mL), respectively. A positive relationship between average, maximum, or minimum plasma concentrations of voriconazole and efficacy was not established during therapeutic studies, nor was such a relationship demonstrated in prophylactic studies.

Pharmacokinetic/pharmacodynamic analysis of data from clinical trials identified a positive association between plasma concentrations of voriconazole and abnormalities in liver function tests as well as visual disturbances. Dose adjustment was not studied in prophylactic trials.

Clinical efficacy and safety. In vitro, voriconazole demonstrates a broad spectrum of antifungal activity against Candida species (including fluconazole-resistant 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 have 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 either partial or complete response) include isolated 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 been demonstrated against various Curvularia species and various Sporothrix species; however, the clinical significance of this activity has not yet been established.

Clinical breakpoints. Prior to initiating therapy, fungal cultures and other appropriate laboratory tests (serological, histopathological) should be obtained to isolate and identify the causative microbial pathogens. Therapy may be initiated before culture and laboratory results are available; however, once these results become available, etiologic therapy 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 various Candida species is not uniform. In particular, for C. glabrata, the MIC of voriconazole is proportionally higher for fluconazole-resistant strains than for fluconazole-susceptible strains. Therefore, every effort should be made to identify Candida to the species level. If results of antifungal susceptibility testing of the pathogen are available, MIC data may be interpreted using susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1

EUCAST Breakpoints

Species of Candida	Breakpoint MIC values (mg/l)
	≤ S (susceptible)	> R (resistant)
Candida albicans1	0.125	0.125
Candida tropicalis1	0.125	0.125
Candida parapsilosis1	0.125	0.125
Candida glabrata2	Insufficient evidence data
Candida krusei3	Insufficient evidence data
Other Candida species4	Insufficient evidence data
1 Strains with MIC values above the susceptibility breakpoint (S) are rare or have not been reported. Identification of any such strains and testing their susceptibility to antimicrobial agents should be repeated, and if the result is confirmed, the strain should be referred to a reference laboratory. 2 In clinical studies, response to voriconazole in patients with infections caused by C. glabrata was 21% lower compared to C. albicans, C. parapsilosis, and C. tropicalis. In vitro data demonstrated a slight increase in resistance of C. glabrata to voriconazole. 3 In clinical studies, response to voriconazole in patients with infections caused by C. krusei was comparable to that seen with C. albicans, C. parapsilosis, and C. tropicalis. However, since only 9 cases of such infection were available for EUCAST analysis, there is currently insufficient evidence to establish clinical susceptibility breakpoints for C. krusei. 4 EUCAST has not defined species-independent susceptibility breakpoints for voriconazole.

Clinical experience of use. Within this section, a favorable outcome of treatment is defined as complete or partial response.

Infections caused by Aspergillus – efficacy in patients with poor-prognosis aspergillosis. Voriconazole demonstrates in vitro fungicidal activity against various species of Aspergillus. The efficacy of voriconazole and its advantages in patient survival compared to standard therapy with amphotericin B as first-line treatment for acute invasive aspergillosis were demonstrated in an open-label, randomized, multicenter study involving 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours for 7 days. The route of administration could then be switched to oral dosing at 200 mg every 12 hours. The median duration of intravenous voriconazole therapy was 10 days (range: 2–85 days). After intravenous treatment, the median duration of oral voriconazole therapy was 76 days (range: 2–232 days).

A favorable overall response (complete or partial resolution of all associated symptoms, signs, and radiographic/bronchoscopic findings present before initiation of treatment) was observed in 53% of patients receiving voriconazole compared to 31% of patients receiving the comparator drug. Patient survival over the 84-day period was statistically significantly higher with voriconazole than with the comparator drug, and clinically and statistically significant advantages of voriconazole were demonstrated both in terms of time to death and time to discontinuation due to toxicity. This study confirmed the results of a previous prospective study in which a positive treatment outcome was observed in patients with risk factors for poor prognosis, including graft-versus-host reaction and particularly cerebral infections (typically associated with 100% mortality). In these studies, the drug was investigated for the treatment of sinus aspergillosis, cerebral, pulmonary, and disseminated aspergillosis in patients following bone marrow and solid organ transplantation, as well as in patients with hematologic malignancies, solid tumors, and AIDS.

Candidemia in non-neutropenic patients. The efficacy of voriconazole compared to a treatment regimen of amphotericin B followed by fluconazole as first-line therapy for candidemia was demonstrated in an open-label comparative study. The study included 370 non-neutropenic patients (aged 12 years and older) with documented candidemia, of whom 248 received voriconazole therapy. Nine patients in the voriconazole group and five patients in the amphotericin B followed by fluconazole group also had mycologically confirmed deep tissue infections. Patients with renal impairment were excluded from the study. The median duration of treatment in both study groups was 15 days. In the primary analysis, favorable response to treatment, as assessed by the Blinded Independent Data Review Committee, was defined as resolution or improvement of all clinical signs and symptoms of infection together with eradication of Candida from blood and infected deep tissue sites 12 weeks after completion of therapy. Patients not evaluable at 12 weeks after completion of therapy were considered treatment failures. Based on this analysis, favorable treatment outcomes were observed in 41% of patients in both treatment groups.

In a secondary analysis using assessments by the Independent Data Review Committee at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after completion of therapy), the rates of favorable response to voriconazole and to amphotericin B followed by fluconazole were 65% and 71%, respectively. The rates of favorable treatment outcomes as assessed by investigators at each of these evaluable time points are presented in Table 2.

Table 2

Time point	Voriconazole (N=248)	Amphotericin B → fluconazole (N=122)
End of therapy	178 (72 %)	88 (72 %)
2 weeks after end of therapy	125 (50 %)	62 (51 %)
6 weeks after end of therapy	104 (42 %)	55 (45 %)
12 weeks after end of therapy	104 (42 %)	51 (42 %)

Severe refractory infections caused by Candida species. In a clinical study involving 55 patients with severe refractory systemic infections caused by Candida species (including candidemia, disseminated candidiasis, and other forms of invasive candidiasis), in whom prior antifungal therapy, including fluconazole, had been ineffective. A favorable response to voriconazole treatment was observed in 24 patients (15 with complete response, 9 with partial response). In patients infected with fluconazole-resistant strains not belonging to Candida albicans, a favorable outcome with voriconazole therapy was observed in 3 out of 3 patients infected with C. krusei (complete response in all) and in 6 out of 8 patients infected with C. glabrata (complete response in 5, partial response in 1). Data on clinical efficacy were supported by limited data on pathogen susceptibility to the drug.

Infections caused by various species of Scedosporium and Fusarium. The efficacy of voriconazole against these rare fungal pathogens has been demonstrated:

• Scedosporium species: a favorable response to voriconazole therapy was observed in 16 out of 28 patients infected with S. apiospermum (6 with complete response, 10 with partial response) and in 2 out of 7 patients infected with S. prolificans (partial response in both). Additionally, a favorable response was observed in 1 out of 3 patients infected with more than one pathogenic organism, including various Scedosporium species;
• Fusarium species: successful therapy with voriconazole was achieved in 7 out of 17 patients (3 complete, 4 partial responses). Among these 7 patients, 3 had ocular infections, 1 had a paranasal sinus infection, and 3 had disseminated infection. Another 4 patients with fusariosis were infected with multiple pathogens, and 2 of these patients had a favorable treatment outcome.

Most patients who received voriconazole for the treatment of the above-mentioned rare fungal infections had prior intolerance or resistance to previously used antifungal agents.

Primary prophylaxis of invasive fungal infections – efficacy in recipients of allogeneic hematopoietic stem cell transplantation without prior confirmed or suspected invasive fungal infection. Voriconazole was compared with itraconazole as a primary prophylactic agent in an open-label, multicenter comparative study in adults and adolescents undergoing allogeneic hematopoietic stem cell transplantation, without prior confirmed or suspected invasive fungal infection. Success was defined as the ability to continue prophylaxis with the study drug for 100 days after hematopoietic stem cell transplantation (continuously for >14 days) and survival without confirmed or suspected invasive fungal infection within 180 days after transplantation. The modified "intention-to-treat" (ITT) population included 465 recipients of allogeneic hematopoietic stem cell transplantation, of whom 45% had acute myeloid leukemia. Conditioning regimens were administered to 58% of all patients. Prophylaxis with the study drug was initiated immediately after hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 patients received itraconazole. The median duration of prophylaxis in the ITT population was 96 days for voriconazole and 68 days for itraconazole. Efficacy rates and other secondary endpoints are presented in Table 3.

Table 3

Study Endpoints	Voriconazole N=224	Itraconazole N=241	Difference in proportions and 95% confidence interval (CI)	P-value
Effectiveness on Day 180*	109 (48.7%)	80 (33.2%)	16.4% (7.7%, 25.1%)**	0.0002**
Effectiveness on Day 100	121 (54.0%)	96 (39.8%)	15.4% (6.6%, 24.2%)**	0.0006**
Duration of prophylaxis with study drug for at least 100 days	120 (53.6%)	94 (39.0%)	14.6% (5.6%, 23.5%)	0.0015
Survival rate up to Day 180	184 (82.1%)	197 (81.7%)	0.4% (–6.6%, 7.4%)	0.9107
Development of proven or suspected invasive fungal infection by Day 180	3 (1.3%)	5 (2.1%)	0.7% (–3.1%, 1.6%)	0.5390
Development of proven or suspected invasive fungal infection by Day 100	2 (0.9%)	4 (1.7%)	0.8% (–2.8%, 1.3%)	0.4589
Development of proven or suspected invasive fungal infection during the period of study drug administration	0	3 (1.2%)	1.2% (–2.6%, 0.2%)	0.0813

• Primary efficacy endpoint of the study.

** Difference in proportions, with 95% CI and P-value, adjusted for randomization.

The incidence rates of invasive fungal infection by day 180 and the primary endpoint of the study, i.e., "efficacy at day 180," for patients with acute myeloid leukemia and conditioning are presented in Tables 4 and 5, respectively.

Table 4

Acute Myeloid Leukemia

Study endpoint	Voriconazole (N=98)	Itraconazole (N=109)	Relative risk difference and 95 % CI
Incidence of invasive fungal infection – day 180	1 (1.0 %)	2 (1.8 %)	–0.8 % (–4.0 %, 2.4 %) **
Efficacy on day 180*	55 (56.1 %)	45 (41.3 %)	14.7 % (1.7 %, 27.7 %)***

* Primary endpoint of the study.

** Demonstrated non-inferiority with a margin of 5%.

*** Differences in ratios and 95% CI obtained after adjustment for randomization.

Table 5

Myeloablative conditioning regimen

Study endpoint	Voriconazole (N=125)	Itraconazole (N=143)	Difference in proportions and 95% CI
Incidence of invasive fungal infection – day 180	2 (1.6%)	3 (2.1%)	0.5% (–3.7%, 2.7%) **
Efficacy on day 180*	70 (56.0%)	53 (37.1%)	20.1% (8.5%, 31.7%)***

* Primary endpoint of the study.

** Demonstrated non-inferiority with a 5% margin.

*** Differences in ratios and 95% CI obtained after adjustment for randomization.

Secondary prophylaxis of invasive fungal infection – efficacy in hematopoietic stem cell transplant recipients with previously confirmed or suspected invasive fungal infection. Voriconazole was evaluated as a secondary prophylactic agent in an open-label, non-comparative, multicenter study in adult recipients of allogeneic hematopoietic stem cell transplantation with previously confirmed or suspected invasive fungal infection. The primary endpoint was the incidence of confirmed or suspected invasive fungal infections during the first year after hematopoietic stem cell transplantation. The ITT population included 40 patients with prior invasive fungal infections, including 31 with aspergillosis, 5 with candidiasis, and 4 with other types of invasive fungal infection. The mean duration of prophylactic treatment with the investigational drug in the ITT population was 95.5 days.

Confirmed or suspected invasive fungal infections occurred in 7.5% (3/40) of patients during the first year after hematopoietic stem cell transplantation, including one case of candidemia, one case of scedosporiosis (both were recurrences of prior invasive fungal infection), and one case of zygomycosis. The survival rate on day 180 was 80.0% (32/40), and over 1 year was 70.0% (28/40).

Duration of therapy. During clinical trials, 705 patients received voriconazole for longer than 12 weeks, and 164 patients for longer than 6 months.

Pediatric population. 53 pediatric patients (aged 2 to 18 years) received voriconazole treatment in two prospective, open-label, non-comparative, multicenter clinical studies. In one study, 31 patients with possible, proven, or probable invasive aspergillosis were enrolled, of whom 14 had proven or probable invasive aspergillosis. These patients were included in the modified intent-to-treat (MITT) efficacy analyses. In the second study, 22 patients with invasive candidiasis, including candidemia and esophageal candidiasis, requiring primary or salvage therapy were enrolled. Of these patients, 17 were included in the MITT efficacy analyses. In patients with invasive aspergillosis, the overall response rate at 6 weeks was 64.3% (9 out of 14); the overall response rate in patients aged 2 to 12 years was 40% (2 out of 5), and in patients aged 12 to 18 years was 77.8% (7 out of 9). In patients with candidemia, the overall response rate at the end of treatment was 85.7% (6 out of 7), and in patients with esophageal candidiasis was 70% (7 out of 10). The overall response rate (in patients with candidemia and esophageal candidiasis combined) was 88.9% (8 out of 9) in patients aged 2 to 12 years and 62.5% (5 out of 8) in patients aged 12 to 18 years.

Clinical studies assessing QTc interval. A placebo-controlled, randomized, crossover study with single-dose administration in healthy volunteers was conducted to evaluate the effect of investigational agents on the QTc interval. Three doses of voriconazole and ketoconazole were administered orally. The placebo-corrected mean maximum increase in QTc interval from baseline was 5.1, 4.8, and 8.2 ms after administration of 800 mg, 1200 mg, and 1600 mg of voriconazole, respectively, and 7.0 ms after administration of 800 mg ketoconazole. No subject had a QTc interval increase ≥ 60 ms from baseline. No subject exceeded the potentially clinically significant threshold of 500 ms.

Pharmacokinetics.

General pharmacokinetic characteristics. Voriconazole pharmacokinetics were studied in healthy volunteers, special patient populations, and patients. After oral administration of 200 mg or 300 mg twice daily for 14 days in patients at high risk of developing aspergillosis (mainly patients with malignancies of lymphatic and hematopoietic tissues), the investigated pharmacokinetic characteristics (rate and extent of absorption, accumulation, and non-linear pharmacokinetics) were similar to those in healthy volunteers.

Voriconazole pharmacokinetics are non-linear due to extensive metabolism. With increasing dose, exposure increases more than proportionally. It is estimated that increasing the oral dose 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 an intravenous dose of 3 mg/kg. An oral loading dose of 300 mg (or 150 mg for patients with body weight below 40 kg) achieves exposure equivalent to an intravenous dose of 4 mg/kg. After administration of oral or intravenous loading doses, plasma concentrations of voriconazole approach steady-state within the first 24 hours of therapy. Without a loading dose regimen, repeated administration of voriconazole twice daily results in accumulation and achievement of steady-state plasma concentrations by day 6 in most patients.

The safe duration of hydroxypropyl beta-cyclodextrin (HPβCD) administration in humans is limited to 21 days (250 mg/kg/day).

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with maximum concentration (Cmax) reached within 1–2 hours. Absolute bioavailability after oral administration is 96%. Repeated administration of voriconazole with a high-fat meal reduces Cmax and AUCτ by 34% and 24%, respectively. Changes in gastric pH do not affect voriconazole absorption.

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

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

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

The main metabolite of voriconazole is the N-oxide, which accounts for 72% of all radiolabeled 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.

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

The elimination half-life (T½) of voriconazole is dose-dependent and is approximately 6 hours after a 200 mg oral dose. Due to non-linear pharmacokinetics, T½ is not used to assess accumulation or elimination of voriconazole.

Pharmacokinetics in special patient populations

Gender. In a multiple-dose oral study, Cmax and AUCτ values in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18–45 years). No statistically significant differences in these parameters were observed between healthy elderly men and women (≥65 years). Dose adjustment based on gender was not performed in clinical studies. Safety profiles and plasma concentrations of the drug in women and men were similar. Therefore, dose adjustment based on gender is not necessary.

Elderly patients. In a clinical study of multiple oral dosing, Cmax and AUCτ values in healthy elderly men (≥65 years) were 61% and 86% higher, respectively, than in healthy young men (18–45 years). No statistically significant differences in Cmax and AUCτ were observed between healthy elderly women (≥65 years) and healthy young women (18–45 years).

Dose adjustment based on age was not performed in clinical studies. A relationship between plasma concentrations and age was observed. Safety profiles of voriconazole in younger and elderly patients were similar; therefore, dose adjustment in elderly patients is not required (see section "Dosage and administration").

Pediatric population. The recommended oral dose for children is based on pharmacokinetic analyses from data obtained in 112 immunocompromised children aged 2–12 years and 26 immunocompromised children aged 12–17 years. Multiple intravenous doses of 3, 4, 6, 7, and 8 mg/kg twice daily and multiple oral doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily (oral suspension powder) were evaluated in three pharmacokinetic studies in children. Loading doses of 6 mg/kg twice daily intravenously on day 1, followed by maintenance doses of 4 mg/kg twice daily intravenously and 300 mg twice daily orally (tablets), were evaluated in one pediatric pharmacokinetic study. This patient group showed higher inter-individual variability compared to adults.

Comparison of pharmacokinetic parameters between children and adults showed that 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 mg/kg and 8 mg/kg twice daily was comparable to AUCτ in adults after intravenous doses of 3 mg/kg and 4 mg/kg twice daily. AUCτ in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults after 200 mg orally twice daily. Exposure after an 8 mg/kg intravenous dose is approximately twice that after a 9 mg/kg oral dose.

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

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

Renal impairment. In patients with normal renal function, the pharmacokinetic profile of hydroxypropyl beta-cyclodextrin (HPβCD), a component of Vfend for infusion, is characterized by a short half-life (1–2 hours) and no accumulation after consecutive daily doses. In healthy volunteers and patients with moderate to severe renal impairment, the majority (>85%) of an 8 g dose of HPβCD is excreted in urine. In patients with mild, moderate, and severe renal impairment, the half-life of HPβCD was approximately 2, 4, and 6 times longer than normal, respectively. In these patients, consecutive infusions may lead to HPβCD accumulation until steady-state is reached. HPβCD is removed by hemodialysis with a clearance of 37.5±24 mL/min.

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

In a clinical study of multiple oral dosing, 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 liver function receiving 200 mg twice daily. Pharmacokinetic data in patients with severe hepatic cirrhosis (Child–Pugh class C) are lacking (see sections "Special precautions" and "Dosage and administration").

Clinical characteristics.

Indications.

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

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

• invasive aspergillosis;
• candidemia without neutropenia;
• severe invasive infections caused by Candida (including C. krusei) resistant to fluconazole;
• severe fungal infections caused by Scedosporium species and Fusarium species.

Vfend 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, or quinidine, or ivabradine, as increased plasma concentrations of these drugs may lead to QTc interval prolongation and, rarely, to ventricular tachycardia of the torsades de pointes type (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with rifampicin, carbamazepine, and phenobarbital, and with St. John's wort, 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 at lower efavirenz doses, see section "Special precautions for use").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily), as administration of such ritonavir doses leads to a significant reduction in voriconazole plasma concentrations in healthy volunteers (for use at lower ritonavir doses, see section "Special precautions for use").
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as increased plasma concentrations of these drugs 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 of voriconazole with naloxegol, a CYP3A4 substrate, as increased naloxegol plasma concentrations may trigger opioid withdrawal symptoms (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of voriconazole with tolvaptan, as strong CYP3A4 inhibitors such as voriconazole significantly increase tolvaptan plasma concentrations (see section "Special precautions for use").
• Concomitant use of voriconazole with lurasidone, as substantial increase in lurasidone exposure may lead to serious adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with venetoclax at the initiation of treatment and during the dose titration phase of venetoclax, as voriconazole is likely to significantly increase venetoclax plasma concentrations 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 6).

Drug interaction studies were conducted in healthy male volunteers receiving oral voriconazole 200 mg twice daily repeatedly until steady state was achieved. The results obtained are also applicable to other patient populations and may be considered relevant for other routes of administration.

Vfend 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, ivabradine), concomitant use is contraindicated.

Information on interactions between voriconazole and other medicinal products is presented in Table 6. The direction of the arrow 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 interactions;
AUCτ – area under the concentration-time curve over the dosing interval;
AUCt – area under the concentration-time curve from time zero to a defined time point;
AUC0–∞ – area under the concentration-time curve from time zero to infinity;
n/a – not applicable.

Interactions in Table 6 are listed in the following order: concomitant use contraindicated, concomitant use requires dose adjustment and careful clinical and biological monitoring, concomitant use has no significant pharmacokinetic interactions but may raise clinical concern in the therapeutic area.

Table 6
[Note: Table 6 content not provided in source text; translation ends here.]

Medicinal product (mechanism of interaction)	Interaction Mean geometric change, %	Recommendations for concomitant use
Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine (CYP3A4 substrates)	Although no specific studies have been conducted, increased plasma concentrations of these agents may lead to QTc prolongation and rarely to development of torsades de pointes ventricular tachycardia	Contraindicated (see section "Contraindications")
Carbamazepine and long-acting barbiturates, e.g., phenobarbital, mephobarbital (potent CYP450 inducers)	Despite lack of specific studies, carbamazepine and long-acting barbiturates are likely to significantly reduce voriconazole plasma concentrations	Contraindicated (see section "Contraindications")
Efavirenz (non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and substrate) 400 mg once daily with voriconazole 200 mg twice daily* 300 mg once daily with 400 mg voriconazole twice daily*	Cmax of efavirenz ↑ 38% AUCτ of efavirenz ↑ 44% Cmax of voriconazole ↓ 61% AUCτ of voriconazole ↓ 77% Compared to 600 mg efavirenz once daily: Cmax of efavirenz ↔ AUCτ of efavirenz ↑ 17% Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 23% AUCτ of voriconazole ↓ 7%	Concomitant use of standard doses of voriconazole with efavirenz 400 mg once daily or higher is contraindicated (see section "Contraindications") When voriconazole and efavirenz are used concomitantly, the maintenance dose of voriconazole should be increased to 400 mg twice daily, and the dose of efavirenz should be reduced to 300 mg once daily. After discontinuation of voriconazole, return to the original efavirenz dose (see sections "Special warnings and precautions for use" and "Dosage and administration")
Ergot alkaloids, e.g., ergotamine and dihydroergotamine (CYP3A4 substrates)	Although specific studies have not been conducted, voriconazole may increase plasma concentrations of ergot alkaloids and lead to ergotism	Contraindicated (see section "Contraindications")
Lurasidone (CYP3A4 substrate)	Although no studies have been conducted, voriconazole is likely to cause a significant increase in lurasidone plasma concentration.	Contraindicated (see section "Contraindications").
Naloxegol (CYP3A4 substrate)	Although no studies have been conducted, voriconazole is likely to cause a significant increase in naloxegol plasma concentration.	Contraindicated (see section "Contraindications").
Rifabutin (potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitant with voriconazole 350 mg twice daily*) 300 mg once daily (concomitant with voriconazole 400 mg twice daily*)	Cmax of voriconazole ↓ 69% AUCτ of voriconazole ↓ 78% Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↓ 4% AUCτ of voriconazole ↓ 32% Cmax of rifabutin ↑ 195% AUCτ of rifabutin ↑ 331% Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 104% AUCτ of voriconazole ↑ 87%	Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk. The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight below 40 kg) (see section "Dosage and administration"). When rifabutin and voriconazole are used concomitantly, careful monitoring of blood counts and rifabutin-related adverse reactions (such as uveitis) is recommended
Rifampicin (600 mg once daily) (potent CYP450 inducer)	Cmax of voriconazole ↓ 93% AUCτ of voriconazole ↓ 96%	Contraindicated (see section "Contraindications")
Ritonavir (protease inhibitor) (potent CYP450 inducer; CYP3A4 inhibitor and substrate) High doses (400 mg twice daily) Low doses (100 mg twice daily)*	Cmax and AUCτ of ritonavir ↔ Cmax of voriconazole ↓ 66% AUCτ of voriconazole ↓ 82% Cmax of ritonavir ↓ 25% AUCτ of ritonavir ↓ 13% Cmax of voriconazole ↓ 24% AUCτ of voriconazole ↓ 39%	Concomitant use of voriconazole and high-dose ritonavir (400 mg or higher twice daily) is contraindicated (see section "Contraindications"). Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless benefit outweighs risk
St. John's wort (CYP450 inducer; P-glycoprotein inducer) 300 mg three times daily (concomitant with single 400 mg voriconazole dose)	In an independent published study, AUC0-∞ of voriconazole ↓ 59%	Contraindicated (see section "Contraindications")
Tolvaptan (CYP3A4 substrate)	Although appropriate clinical studies have not been conducted, voriconazole is likely to significantly increase plasma concentrations of tolvaptan.	Contraindicated (see section "Contraindications").
Venetoclax (CYP3A substrate)	Although no studies have been conducted, voriconazole is likely to significantly increase venetoclax plasma concentrations.	Concomitant use of voriconazole is contraindicated at the initiation of venetoclax treatment and during the dose titration phase (see section "Contraindications"). Dose reduction of venetoclax is required as specified in the venetoclax product information during stable daily dosing; careful monitoring for signs of toxicity is recommended.
Fluconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4), 200 mg once daily	Cmax of voriconazole ↑ 57% AUCτ of voriconazole ↑ 79% Cmax of fluconazole – not known AUCτ of fluconazole – not known	It is not established what dose reduction and/or frequency adjustment of voriconazole and fluconazole is necessary to avoid this effect. When voriconazole is administered after fluconazole, monitoring for adverse reactions associated with voriconazole is recommended
Phenytoin (CYP2C9 substrate and potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitant with 400 mg voriconazole twice daily)*	Cmax of voriconazole ↓ 49% AUCτ of voriconazole ↓ 69% Cmax of phenytoin ↑ 67% AUCτ of phenytoin ↑ 81% Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 34% AUCτ of voriconazole ↑ 39%	Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk. When phenytoin and voriconazole are used concomitantly, careful monitoring of plasma phenytoin levels is recommended. Phenytoin may be used concomitantly with voriconazole provided the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily or from 200 mg to 400 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight below 40 kg) (see section "Dosage and administration")
Letermovir (inducer of CYP2C9 and CYP2C19)	Cmax of voriconazole ↓ 39% AUC0-12 of voriconazole ↓ 44% C12 of voriconazole ↓ 51%	If concomitant use of voriconazole with letermovir cannot be avoided, monitor for loss of voriconazole efficacy
Glasdegib (CYP3A4 substrate)	Although no studies have been conducted, voriconazole is likely to significantly increase plasma concentrations of glasdegib and increase the risk of QTc prolongation.	If concomitant use cannot be avoided, frequent ECG monitoring is recommended (see section "Special warnings and precautions for use").
Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 substrates)	Although no studies have been conducted, voriconazole is likely to significantly increase plasma concentrations of tyrosine kinase inhibitors metabolized by CYP3A4.	If concomitant use cannot be avoided, dose reduction of tyrosine kinase inhibitors is recommended (see section "Special warnings and precautions for use").
Anticoagulants Warfarin (CYP2C9 substrate) (single 30 mg dose of warfarin concomitant with 300 mg voriconazole twice daily) Other oral coumarins, such as phenprocoumon, acenocoumarol (CYP2C9 and CYP3A4 substrates)	Maximum prothrombin time approximately doubled Although specific studies have not been conducted, voriconazole may increase plasma concentrations of coumarins and thereby prolong prothrombin time	Close monitoring of prothrombin time and other appropriate coagulation parameters is recommended, with appropriate anticoagulant dose adjustments
Ivacaftor (CYP3A4 substrate)	Although appropriate clinical studies have not been conducted, voriconazole is likely to increase plasma concentrations of ivacaftor, increasing the risk of adverse reactions	Dose reduction of ivacaftor is recommended
Benzodiazepines, e.g., midazolam, triazolam, alprazolam (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole is likely to increase plasma concentrations of benzodiazepines metabolized by CYP3A4 and prolong sedative effects	Consideration should be given to reducing benzodiazepine doses
Immunosuppressants (CYP3A4 substrates) Sirolimus (single 2 mg dose) Everolimus (CYP3A4 substrate, P-glycoprotein substrate) Cyclosporine (in stable renal transplant recipients on continuous cyclosporine therapy) Tacrolimus (single 0.1 mg/kg dose)	In an independent published study: Cmax of sirolimus ↑ 6.6-fold, AUC0-∞ of sirolimus ↑ 11-fold Although no studies have been conducted, voriconazole is likely to significantly increase plasma concentrations of everolimus Cmax of cyclosporine ↑ 13% AUCτ of cyclosporine ↑ 70% Cmax of tacrolimus ↑ 117% AUCt of tacrolimus ↑ 221%	Concomitant use contraindicated (see section "Contraindications") Concomitant use of everolimus and voriconazole is not recommended, as voriconazole may cause a significant increase in everolimus concentration (see section "Special warnings and precautions for use") In patients already receiving cyclosporine, initiation of voriconazole therapy requires a 50% reduction in cyclosporine dose and close monitoring of cyclosporine levels. Elevated cyclosporine levels are associated with nephrotoxic effects. After discontinuation of voriconazole, cyclosporine levels should be closely monitored and dose increased if necessary In patients already receiving tacrolimus, initiation of voriconazole therapy requires reduction of tacrolimus dose to one-third of the initial dose and close monitoring of tacrolimus levels. Elevated tacrolimus levels are associated with nephrotoxic effects. After discontinuation of voriconazole, tacrolimus levels should be closely monitored and dose increased if necessary
Long-acting opioids (CYP3A4 substrates) Oxycodone (10 mg single dose)	In an independent published study: Cmax of oxycodone ↑ 1.7-fold, AUC0-∞ of oxycodone ↑ 3.6-fold	Consideration should be given to reducing the dose of oxycodone and other CYP3A4-metabolized long-acting opioids (e.g., hydrocodone). Frequent monitoring for opioid-related adverse reactions is recommended
Methadone (CYP3A4 substrate) (32-100 mg once daily)	Cmax of R-methadone (active) ↑ 31% AUCτ of R-methadone (active) ↑ 47% Cmax of S-methadone ↑ 65% AUCτ of S-methadone ↑ 103%	Continuous monitoring for adverse reactions and toxic effects associated with increased methadone plasma concentrations, including QT prolongation, is recommended. Dose reduction of methadone may be necessary
Nonsteroidal anti-inflammatory drugs (NSAIDs) (CYP2C9 substrates) Ibuprofen (400 mg single dose) Diclofenac (50 mg single dose)	Cmax of S-ibuprofen ↑ 20% AUC0-∞ of S-ibuprofen ↑ 100% Cmax of diclofenac ↑ 114% AUC0-∞ of diclofenac ↑ 78%	Frequent monitoring for NSAID-related adverse reactions and toxicity is recommended. Dose adjustment of NSAIDs may be necessary
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) 40 mg once daily*	Cmax of omeprazole ↑ 116% AUCτ of omeprazole ↑ 280% Cmax of voriconazole ↑ 15% AUCτ of voriconazole ↑ 41% Metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole, leading to increased plasma concentrations	Dose adjustment of voriconazole is not recommended. In patients already receiving omeprazole (40 mg or higher), initiation of voriconazole therapy requires a 50% reduction in omeprazole dose
Oral contraceptives (CYP3A4 substrates, CYP2C19 inhibitors) Norethisterone/ethinylestradiol (1 mg/0.035 mg once daily)	Cmax of ethinylestradiol ↑ 36% AUCτ of ethinylestradiol ↑ 61% Cmax of norethisterone ↑ 15% AUCτ of norethisterone ↑ 53% Cmax of voriconazole ↑ 14% AUCτ of voriconazole ↑ 46%	Frequent monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended
Short-acting opioids (CYP3A4 substrates) Alfentanil (20 μg/kg single dose, concomitant with naloxone) Fentanyl (5 μg/kg single dose)	In an independent published study: AUC0-∞ of alfentanil ↑ 6-fold In an independent published study: AUC0-∞ of fentanyl ↑ 1.34-fold	Consideration should be given to reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil). Frequent monitoring for respiratory depression and opioid-related adverse reactions is recommended
Statins, e.g., lovastatin (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole is likely to increase plasma levels of statins metabolized by CYP3A4, potentially leading to rhabdomyolysis	If concomitant use of voriconazole with CYP3A4-metabolized statins cannot be avoided, consider reducing the statin dose.
Sulfonylurea derivatives, e.g., tolbutamide, glipizide, glyburide (CYP2C9 substrates)	Although specific studies have not been conducted, voriconazole may increase plasma levels of sulfonylurea derivatives and thereby cause hypoglycemia	Close monitoring of blood glucose levels is required. Consideration should be given to reducing the dose of sulfonylurea derivatives
Vinca alkaloids, e.g., vincristine and vinblastine (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole is known to increase plasma levels of vinca alkaloids and lead to neurotoxic effects	Consideration should be given to reducing the dose of vinca alkaloids
Other HIV protease inhibitors, e.g., saquinavir, amprenavir, nelfinavir* (CYP3A4 inhibitors)	Clinical studies have not been conducted. In vitro studies indicate that voriconazole may inhibit the metabolism of HIV protease inhibitors and that voriconazole metabolism may be inhibited by HIV protease inhibitors	Close monitoring for signs of toxicity and/or lack of efficacy of these agents is recommended, along with consideration of dose adjustment
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs), e.g., delavirdine, nevirapine (CYP3A4 substrates and inhibitors or CYP450 inducers)	Clinical studies have not been conducted. In vitro studies indicate that voriconazole metabolism may be inhibited by NNRTIs and that voriconazole may inhibit NNRTI metabolism. Based on the effect of efavirenz on voriconazole, voriconazole metabolism may be induced by NNRTIs	Close monitoring for signs of toxicity and/or lack of efficacy of these agents is recommended, along with consideration of dose adjustment
Tretinoin (CYP3A4 substrate)	Although no studies have been conducted, voriconazole is likely to significantly increase plasma concentrations of tretinoin and increase the risk of adverse reactions (pseudotumor cerebri, hypercalcemia).	Dose adjustment of tretinoin is recommended during and after treatment with voriconazole.
Cimetidine (non-specific CYP450 inhibitor and increases gastric pH) (400 mg twice daily)	Cmax of voriconazole ↑ 18% AUCτ of voriconazole ↑ 23%	No dose adjustment required
Digoxin (P-glycoprotein substrate) (0.25 mg once daily)	Cmax of digoxin ↔ AUCτ of digoxin ↔	No dose adjustment required
Indinavir (CYP3A4 inhibitor and substrate) (800 mg three times daily)	Cmax of voriconazole ↔ AUCτ of voriconazole ↔ Cmax of indinavir ↔ AUCτ of indinavir ↔	No dose adjustment required
Macrolide antibiotics Erythromycin (CYP3A4 inhibitor) (1 g twice daily) Azithromycin (500 mg once daily)	Cmax and AUCτ of voriconazole ↔ Cmax and AUCτ of voriconazole ↔ Effect of voriconazole on erythromycin or azithromycin unknown	No dose adjustment required
Mycophenolic acid (UDP-glucuronosyltransferase substrate) (1 g single dose)	Cmax and AUCt of mycophenolic acid ↔	No dose adjustment required
Corticosteroids Prednisolone (CYP3A4 substrate) (60 mg single dose)	Cmax of prednisolone ↑ 11% AUC0-∞ of prednisolone ↑ 34%	No dose adjustment required Patients receiving long-term voriconazole and corticosteroid therapy (including inhaled corticosteroids such as budesonide and intranasal corticosteroids) should be closely monitored for adrenal dysfunction during and after discontinuation of voriconazole (see section "Special warnings and precautions for use").
Ranitidine (increases gastric pH) (150 mg twice daily)	Cmax and AUCτ of voriconazole ↔	No dose adjustment required
Flucloxacillin [CYP450 inducer]	Significant reduction in voriconazole plasma concentration has been reported.	If concomitant use of voriconazole with flucloxacillin cannot be avoided, monitoring for potential loss of voriconazole efficacy (e.g., via therapeutic drug monitoring) is recommended; voriconazole dose increase may be necessary.

Special precautions for use.

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

Duration of use. The medicinal product should not be administered intravenously for longer than 6 months.

Cardiovascular system. Voriconazole is associated with QTc interval prolongation. Rare cases of ventricular tachycardia of the "torsades de pointes" type have been observed in patients with risk factors such as prior cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant therapy with medicinal products that may induce the aforementioned 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 arrhythmia;
• concomitant use of medicinal products that may prolong the QTc interval.

Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and, if necessary, corrected prior to initiation of voriconazole and during treatment (see section "Method of administration and dosage"). A study evaluating the effect on QTc interval after single doses of voriconazole up to 4 times the standard daily dose was conducted in healthy volunteers. In none of the study participants 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 intravenous 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 evident hepatitis, cholestasis, and fulminant hepatic failure, some with fatal outcome) were observed with voriconazole use. Hepatic reactions occurred primarily in patients with severe underlying conditions (especially hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, were observed in patients without other identified risk factors. Liver function abnormalities were reversible and typically 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 AST and ALT) at the start of Vizol treatment and at least once weekly during the first month of therapy. Treatment duration should be as short as possible; however, if treatment continues based on a risk-benefit assessment (see section "Method of administration and dosage"), the frequency of monitoring may be reduced to once monthly in the absence of changes in liver function tests.

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

Liver function monitoring is required for both children and adults.

Serious cutaneous adverse reactions

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

Adrenal gland effects

Cases of adrenal insufficiency have been reported with use of other azoles (including voriconazole).

Reversible adrenal insufficiency has been documented in patients receiving voriconazole.

Adrenal insufficiency has been reported in patients receiving azoles, with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients receiving corticosteroids, voriconazole-associated inhibition of CYP3A4 metabolism may lead to corticosteroid excess and adrenal suppression (see section "Special precautions for use"). Cases of Cushing's syndrome, with or without subsequent adrenal insufficiency, have been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients receiving long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids such as budesonide and intranasal corticosteroids) should be closely monitored for adrenal cortex dysfunction both during treatment and upon discontinuation of voriconazole (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be instructed to seek immediate medical attention if signs and symptoms of Cushing's syndrome or adrenal insufficiency develop.

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

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

In patients who have undergone organ transplantation, non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed. If a patient develops skeletal pain and radiological findings suggest periostitis, multidisciplinary medical consultations should be conducted and discontinuation of Vizol should be considered.

Ocular adverse reactions. Prolonged adverse reactions affecting the eyes, 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 in severely ill patients receiving voriconazole. Renal function may decrease 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. The safety and efficacy of voriconazole in children under 2 years of age have not been established (see sections "Pharmacodynamics" and "Adverse reactions"). Voriconazole is recommended for use in children aged 2 years and older. Elevated liver enzyme levels occur more frequently in children (see section "Adverse reactions"). Liver function monitoring is required for both adults and children. In patients aged 2–12 years, oral bioavailability of the drug may be limited due to malabsorption and very low body weight. Intravenous administration is recommended for such patients.

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

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). Close monitoring of plasma phenytoin levels is recommended when phenytoin and voriconazole are used concomitantly. 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 should be reduced to 300 mg every 24 hours (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage").

Rifabutin (potent CYP450 inducer). Close monitoring of complete blood count parameters and rifabutin-related adverse reactions (such as uveitis) is required when voriconazole and rifabutin are used concomitantly. 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 significantly increase everolimus concentrations. Insufficient data are currently available regarding dosage adjustments (see section "Interaction with other medicinal products and other forms of interaction").

Naloxegol (CYP3A4 substrate). Concomitant use of naloxegol and voriconazole is not recommended, as voriconazole is expected to significantly increase naloxegol concentrations. Insufficient data are currently available to recommend naloxegol dosing in this situation (see section "Interaction with other medicinal products and other forms of interaction").

Methadone (CYP3A4 substrate). Careful monitoring for adverse reactions and signs of methadone toxicity (including QTc interval prolongation) is recommended when methadone and voriconazole are used concomitantly, 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 (such as sufentanil) should be considered (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of opioid-related adverse reactions (including prolonged respiratory function monitoring) may be necessary, as the half-life of alfentanil is prolonged fourfold with concomitant voriconazole use, and published data from one study indicate that concomitant use of fentanyl and voriconazole increases 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 CYP3A4-metabolized long-acting opioids (e.g., hydrocodone) should be considered. Frequent 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").

Use during pregnancy or breastfeeding.

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

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

Vizol 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 in breast milk has not been studied; therefore, breastfeeding should be discontinued during treatment with Vizol.

Fertility. Animal studies did not demonstrate impaired fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

Voriconazole has a moderate effect on the ability to drive and operate machinery. The drug 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 vehicles or operating machinery.

Method of Administration and Dosage

Before initiating treatment with Vizol and during its administration, monitoring for electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia is required, with correction as necessary (see section "Special Warnings and Precautions for Use").

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

Treatment

Adults. To achieve on the first day plasma concentrations close to steady-state levels, therapy with Vizol should be initiated according to an appropriate loading dose regimen, administered either orally or intravenously. Due to the high oral bioavailability of voriconazole (96%), the route of administration may be switched from intravenous to oral or vice versa, as clinically indicated. Detailed dosage recommendations are provided in Table 7.

Table 7

Dosing regimen	Intravenous	Oral
		Patients with body weight 40 kg or more*	Patients with body weight less than 40 kg*
Loading doses (within the first 24 hours of treatment)	6 mg/kg every 12 hours	400 mg every 12 hours	200 mg every 12 hours
Maintenance doses (after 24 hours from start of treatment)	4 mg/kg twice daily	200 mg twice daily	100 mg twice daily

* Including patients aged 15 years and older.

Duration of treatment. The duration of treatment 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 "Pharmacodynamics" and "Special precautions").

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 dose may be increased to 150 mg orally twice daily.

For patients who cannot tolerate higher doses of the drug, the dose should be gradually reduced by 50 mg until reaching a maintenance dose of 200 mg orally twice daily (or 100 mg orally twice daily 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 "Pharmacodynamics" and "Adverse reactions").

Dose adjustment when used concomitantly with other agents. Rifabutin or phenytoin may be used concomitantly with voriconazole provided that the maintenance dose of voriconazole is increased to 5 mg/kg twice daily intravenously (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Efavirenz may be used concomitantly 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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

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

Renal impairment

In patients with moderate to severe renal impairment (creatinine clearance <50 ml/min), accumulation of hydroxypropyl betadex occurs. Voriconazole should be administered orally to these patients, except when the benefit of intravenous voriconazole outweighs the risks. These patients require careful monitoring of serum creatinine levels. If serum creatinine increases, consideration should be given to switching the route of voriconazole administration to oral (see section "Pharmacokinetics").

The clearance of voriconazole during hemodialysis is 121 ml/min. The amount of voriconazole removed during a 4-hour hemodialysis session is insufficient to necessitate dose adjustment.

The clearance of hydroxypropyl betadex 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 voriconazole 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 [ALP], and total bilirubin more than 5 times the upper limit of normal) is limited.

Voriconazole use 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 when the benefit outweighs the potential risk. Close monitoring for toxic effects of the drug is required in patients with severe hepatic impairment (see section "Adverse reactions").

Method of administration

Before administration as an intravenous infusion, the drug must be reconstituted and diluted. Vizol is not intended for bolus injection.

To obtain 20 ml of 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 Vizol vial if the solvent is not 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 product is intended for single use only; only clear solutions free from mechanical particles should be administered.

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

Table 8

Required volumes of Vizol concentrate (10 mg/ml)

Body weight (kg)	Volume of Visol concentrate (10 mg/ml) required to obtain:
	Dose of 3 mg/kg (number of vials)	Dose of 4 mg/kg (number of vials)	Dose of 6 mg/kg (number of vials)	Dose of 8 mg/kg (number of vials)	Dose of 9 mg/kg (number of vials)
10		4.0 ml (1)		8.0 ml (1)	9.0 ml (1)
15		6.0 ml (1)		12.0 ml (1)	13.5 ml (1)
20		8.0 ml (1)		16.0 ml (1)	18.0 ml (1)
25		10.0 ml (1)		20.0 ml (1)	22.5 ml (1)
30	9.0 ml (1)	12.0 ml (1)	18.0 ml (1)	24.0 ml (2)	27.0 ml (2)
35	10.5 ml (1)	14.0 ml (1)	21.0 ml (2)	28.0 ml (2)	31.5 ml (2)
40	12.0 ml (1)	16.0 ml (1)	24.0 ml (2)	32.0 ml (2)	36.0 ml (2)
45	13.5 ml (1)	18.0 ml (1)	27.0 ml (2)	36.0 ml (2)	40.5 ml (3)
50	15.0 ml (1)	20.0 ml (1)	30.0 ml (2)	40.0 ml (2)	45.0 ml (3)
55	16.5 ml (1)	22.0 ml (2)	33.0 ml (2)	44.0 ml (3)	49.5 ml (3)
60	18.0 ml (1)	24.0 ml (2)	36.0 ml (2)	48.0 ml (3)	54.0 ml (3)
65	19.5 ml (1)	26.0 ml (2)	39.0 ml (2)	52.0 ml (3)	58.5 ml (3)
70	21.0 ml (2)	28.0 ml (2)	42.0 ml (3)
75	22.5 ml (2)	30.0 ml (2)	45.0 ml (3)
80	24.0 ml (2)	32.0 ml (2)	48.0 ml (3)
85	25.5 ml (2)	34.0 ml (2)	51.0 ml (3)
90	27.0 ml (2)	36.0 ml (2)	54.0 ml (3)
95	28.5 ml (2)	38.0 ml (2)	57.0 ml (3)
100	30.0 ml (2)	40.0 ml (2)	60.0 ml (3)

The reconstituted solution may be diluted with:

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

Chemical and physical stability of the reconstituted product has been demonstrated for 24 hours at 2–8 °C.

Chemical and physical stability of the diluted product has been demonstrated for 6 hours at 25 °C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.

Prophylaxis in adults and children

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

Dosage. The recommended dosage regimen for prophylaxis is the same as for treatment in the respective age groups (see Tables 7 and 8).

Duration of prophylaxis. The safety and efficacy of voriconazole use for more than 180 days have not been adequately studied in clinical trials.

The use of voriconazole for prophylaxis beyond 180 days (6 months) requires careful benefit-risk assessment.

The following information applies to both treatment and prophylaxis

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

Children.

The medicinal product is administered to children aged 2 years and older. Safety and efficacy of voriconazole 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 9

Dosing regimen	Intravenous	Oral
Loading dose (within the first 24 hours)	9 mg/kg every 12 hours	Not recommended
Maintenance dose (after the first 24 hours)	8 mg/kg twice daily	9 mg/kg twice daily (maximum dose is 350 mg twice daily)

It is recommended to initiate therapy with intravenous administration, and the possibility of switching to oral administration should be considered only after achieving significant clinical improvement. It should be noted that the intravenous dose of 8 mg/kg provides approximately twice the voriconazole exposure compared to the oral dose of 9 mg/kg.

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

Dose selection for pediatric patients aged 2–12 years and for 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 the treatment, the intravenous dose of Vizol should be reduced by 1 mg/kg.

The use of the drug in pediatric patients aged 2–12 years with renal or hepatic impairment has not been studied (see sections “Pharmacokinetics” and “Adverse Reactions”).

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 to voriconazole.

Voriconazole clearance during hemodialysis is 121 mL/min. Hydroxypropyl betadex clearance during hemodialysis is 37.5 ± 24 mL/min.

In cases of overdose, hemodialysis may aid in the elimination of voriconazole and hydroxypropyl betadex from the body.

Adverse Reactions

The safety profile of voriconazole in adults is based on data from an integrated safety database encompassing over 2000 individuals (including 1603 adult patients who participated in therapeutic studies) and an additional 270 adult patients from prophylaxis trials. This patient group is sufficiently diverse and includes patients with hematological malignancies, HIV-infected patients with esophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidemia or aspergillosis, and healthy volunteers.

The most commonly reported adverse reactions included visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, 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.

Since most of the studies were open-label, all adverse reactions potentially causally related to the drug are listed below. Adverse reactions are based on pooled data from 1873 adult patients who participated in therapeutic (1603) and prophylaxis (270) studies. Adverse reactions are categorized by system organ class and frequency: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated based on available information). 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 squamous cell carcinoma in situ of the skin, or Bowen’s disease)*.

Blood and lymphatic system disorders

Common: Agranulocytosis¹, pancytopenia, thrombocytopenia², leukopenia, anemia.

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 edema.

Common: Hypoglycemia, hypokalemia, hyponatremia.

Psychiatric disorders

Common: Depression, hallucinations, anxiety, insomnia, agitation, confusion.

Central nervous system disorders

Very common: Headache.

Common: Seizures, syncope, tremor, hypertension³, paresthesia, somnolence, dizziness.

Uncommon: Cerebral edema, encephalopathy⁴, extrapyramidal disorders⁵, peripheral neuropathy, ataxia, hypesthesia, dysgeusia.

Rare: Hepatic encephalopathy, Guillain-Barré syndrome, nystagmus.

Eye disorders

Very common: Visual disturbances⁶.

Common: Retinal hemorrhage.

Uncommon: Optic nerve disorders⁷, optic disc edema⁸, 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 ventricular tachycardia, complete atrioventricular block, bundle branch block, nodal rhythm.

Vascular disorders

Common: Arterial hypotension, phlebitis.

Uncommon: Thrombophlebitis, lymphangitis.

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnea⁹.

Common: Acute respiratory distress syndrome, pulmonary edema.

Gastrointestinal disorders

Very common: Diarrhea, vomiting, abdominal pain, nausea.

Common: Cheilitis, dyspepsia, constipation, gingivitis.

Uncommon: Peritonitis, pancreatitis, tongue edema, duodenitis, gastroenteritis, glossitis.

Hepatobiliary disorders

Very common: Abnormal liver function tests.

Common: Jaundice, cholestatic jaundice, hepatitis¹⁰.

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 syndrome⁸, photosensitivity, purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema.

Rare: Toxic epidermal necrolysis⁸, drug reaction with eosinophilia and systemic symptoms (DRESS)⁸, angioedema, 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, hematuria.

Uncommon: Renal tubular necrosis, proteinuria, nephritis.

General disorders and administration site conditions

Very common: Fever.

Common: Chest pain, facial edema¹¹, asthenia, chills.

Uncommon: Infusion site reaction, influenza-like illness.

Investigations

Common: Increased blood creatinine levels.

Uncommon: Increased blood urea levels, increased blood cholesterol levels.

* Adverse reactions identified after market release of voriconazole.

1 Includes febrile neutropenia and neutropenia.

2 Includes immune thrombocytopenic purpura.

3 Includes nuchal rigidity and tetany.

4 Includes hypoxic-ischemic encephalopathy and metabolic encephalopathy.

5 Includes akathisia and parkinsonism.

6 See the section "Visual disturbances" under "Adverse Reactions".

7 Optic neuritis of prolonged duration has been reported post-marketing (see section "Special Warnings and Precautions for Use").

8 See section "Special Warnings and Precautions for Use".

9 Includes dyspnea, including dyspnea on exertion.

10 Includes drug-induced liver injury, toxic hepatitis, hepatocellular injury, and hepatotoxicity.

11 Includes periorbital edema, lip swelling, and mouth swelling.

Description of selected adverse reactions

Visual disturbances. Visual disturbances (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorders, halos in the visual field, night blindness, oscillopsia, photopsia, flickering scotoma, reduced visual acuity, visual brightness, visual field defects, floaters in the vitreous body, and xanthopsia) were very commonly observed during clinical and therapeutic trials and were associated with voriconazole use. These visual disturbances were transient and fully reversible, resolving spontaneously within 60 minutes in most cases. No clinically significant long-term visual effects were observed. With repeated dosing, symptoms tended to diminish. Visual disturbances were generally mild, rarely led to drug discontinuation, and were not associated with long-term residual 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 was associated with reduced wave amplitudes on electroretinogram during a clinical study assessing the effect of voriconazole on retinal function in healthy volunteers. Electroretinography measures the electrical potentials of the retina. Changes on electroretinogram did not progress over 29 days of therapy and fully resolved after discontinuation of voriconazole.

Post-marketing reports have described prolonged visual adverse reactions (see section "Special Warnings and Precautions for Use").

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

Patients should be closely monitored for skin reactions, and if lesions progress, Vizol should be discontinued.

Cases of serious photosensitivity reactions, including freckles, lentigo, and actinic keratosis, have been reported, particularly during prolonged treatment (see section "Special Warnings and Precautions for Use").

Cases of cutaneous squamous cell carcinoma (including 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 the clinical program, 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 therapy 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 adjustment, including discontinuation of the drug.

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").

Reactions related to intravenous infusion. Anaphylactoid-type reactions have been reported, including flushing, fever, increased sweating, tachycardia, chest tightness, dyspnea, syncope, nausea, pruritus, and rash. Symptoms occurred immediately after the start of infusion (see section "Special Warnings and Precautions for Use").

Prophylaxis. In an open-label, multicenter comparative study of voriconazole versus itraconazole for primary prophylaxis in adult and adolescent recipients of allogeneic hematopoietic stem cell transplantation without prior confirmed or suspected invasive fungal infection, treatment discontinuation due to adverse reactions occurred in 39.3% of patients in the voriconazole group compared to 39.6% in the itraconazole group. Treatment-related liver adverse reactions led to complete discontinuation of the investigational drug in 50 patients (21.4%) receiving voriconazole and in 18 patients (7.1%) receiving itraconazole.

Pediatric population. The safety of voriconazole was evaluated in 288 children aged 2–12 years (169) and 12–18 years (119), who received voriconazole for prophylaxis (183) and therapy (105) in clinical trials. Safety was also assessed in 158 children aged 2–12 years in compassionate-use programs. Overall, the safety profile of voriconazole in children was similar to that in adults. However, a trend toward more frequent elevation of liver enzymes in children compared to adults was observed (incidence of transaminase elevation was 14.2% in children versus 5.3% in adults), reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the incidence of skin adverse reactions (especially erythema) may be somewhat higher in children than in adults. In 22 patients under 2 years of age treated with voriconazole in compassionate-use programs, the following adverse reactions, which cannot exclude a causal relationship with voriconazole, were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), increased blood bilirubin (1), elevated liver enzymes (1), rash (1), and optic disc edema (1). Pancreatitis has also been reported in children during post-marketing use of voriconazole.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. 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.

Storage conditions.

The medicinal product does not require special storage conditions. Store in a place inaccessible to children.

Incompatibilities.

Infusion of Vizol must not be administered simultaneously with other intravenous medicinal products using the same infusion line or cannula. The container must be inspected to ensure that the infusion is complete. After completion of Vizol infusion, the infusion line may be used for intravenous administration of other medicinal products.

Blood products and short-term infusions of concentrated electrolyte solutions. Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration"). Vizol 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. Total parenteral nutrition should not be interrupted during Vizol administration but must be administered through a separate infusion line. When using a multi-lumen catheter, total parenteral nutrition should be administered through a separate port, not through the port used for Vizol infusion. The medicinal product must not be diluted 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 per carton.

Prescription status. Prescription only.

Manufacturer.

ACCORD HEALTHCARE LIMITED.

Manufacturer’s address and place of business.

GROUND FLOOR, SAGE HOUSE, 319 PINNER ROAD, HARROW, HA1 4HF, United Kingdom.

Marketing Authorization Holder. Accord Healthcare S.L.U.

Inquiries regarding substandard quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected].

Address of the Marketing Authorization Holder. World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.