Voriconazole zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORICONAZOLE ZENTIVA

Composition:

Active ingredient: voriconazole;

1 vial contains 200 mg of voriconazole;

Excipients: hydroxypropyl-beta-cyclodextrin, sodium chloride, hydrochloric acid concentrated (for pH adjustment).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: lyophilized powder, white to almost white.

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

Pharmacokinetics/Pharmacodynamics. In clinical studies, the median steady-state and peak plasma concentrations for individual patients 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 mean, peak, or trough plasma concentrations of voriconazole and efficacy has not been established in therapeutic trials, nor has such a relationship been 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. Voriconazole demonstrates in vitro 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 shows in vitro fungicidal activity against emerging pathogenic fungi, including Scedosporium and Fusarium species, which often exhibit limited susceptibility to existing antifungal agents.

Clinical efficacy (defined as partial or complete response) of voriconazole has been demonstrated against various Aspergillus species, including A. flavus, A. fumigatus, A. terreus, A. niger, and A. nidulans; various Candida species, including C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis; limited numbers 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 responsive to voriconazole (often with 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 and 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 microorganisms. Empirical therapy may be initiated before culture and laboratory results are available; however, once results are obtained, targeted antimicrobial therapy should be adjusted accordingly.

Species most commonly causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei, all of which have voriconazole minimum inhibitory concentrations (MICs) below 1 mg/L.

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

EUCAST Clinical Breakpoints

Table 1

Species of Candida and Aspergillus	Minimum inhibitory concentration (MIC) breakpoint values (mg/l)
	≤ S (susceptible)	> R (resistant)
Candida albicans1	0.06	0.25
Candida dubliniensis1	0.06	0.25
Candida glabrata	Insufficient data (ID)	ID
Candida krusei	ID	ID
Candida parapsilosis1	0.125	0.25
Candida tropicalis1	0.125	0.25
Candida guilliermondii2	ID	ID
Non-species-related breakpoints for Candida3	ID	ID
Aspergillus fumigatus4	1	1
Aspergillus nidulans4	1	1
Aspergillus flavus	ID5	ID5
Aspergillus niger	ID5	ID5
Aspergillus terreus	ID5	ID5
Non-species-related breakpoints6	ID	ID
1 Isolates with MIC values above the susceptible/intermediate (S/I) breakpoint are rare or have not yet been reported. Any such isolate should be re-identified and susceptibility testing repeated; if results are confirmed, the isolate should be referred to a reference laboratory. The isolate should be considered resistant until clinical evidence demonstrates response to isolates with MICs above the current resistance breakpoint. For infections caused by the species listed below, clinical response was achieved in 76% of cases when MICs were at or below the epidemiological cutoff value. Therefore, wild-type populations of C. albicans, C. dubliniensis, C. parapsilosis, and C. tropicalis are considered susceptible. 2 Epidemiological cutoff values (ECOFFs) for these species are generally higher than for C. albicans. 3 Non-species-related breakpoints were established primarily based on PK/PD data and do not depend on the MIC distribution of a specific Candida species. They are used only for organisms lacking their own specific breakpoints. 4 The technical uncertainty zone (TUZ) is 2. Report as “R” with the following note: “In certain clinical situations (non-invasive forms of infection), voriconazole may be used provided adequate exposure is ensured.” 5 ECOFFs for these species are generally one doubling dilution higher than for A. fumigatus. 6 Non-species-related breakpoints have not been established.

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

Infections caused by Aspergillus – efficacy in patients with aspergillosis with poor prognosis. 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 prior to initiation of therapy) 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 results from a previous prospective study, which showed a positive outcome of treatment in patients with risk factors for poor prognosis, including graft-versus-host disease and particularly cerebral infections (typically associated with 100% mortality). In these studies, the drug was investigated in the treatment of sinus aspergillosis, cerebral, pulmonary, and disseminated aspergillosis in patients after bone marrow and solid organ transplantation, in patients with hematological 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 not included in 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/disappearance 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. Outcomes in patients not evaluable at 12 weeks after completion of therapy were considered unfavorable. Based on this analysis, a favorable treatment outcome was 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 end of therapy), the rates of favorable response to voriconazole therapy and to amphotericin B followed by fluconazole were 65% and 71%, respectively. The rates of favorable treatment outcome 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. A clinical study included 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 (complete response in 15, partial response in 9). In patients infected with fluconazole-resistant non-Candida albicans species, favorable outcomes with voriconazole therapy were 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 Scedosporium and Fusarium species. 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 (complete response in 6 patients, partial response in 10) 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 sinus infection, and 3 had disseminated disease. Four additional patients with fusariosis were infected with multiple pathogens; a favorable treatment outcome was observed in 2 of these patients.

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

Primary prophylaxis of invasive fungal infections – efficacy in hematopoietic stem cell transplant recipients 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 post-transplant (continuously for >14 days) and survival without confirmed or suspected invasive fungal infection within 180 days post-transplant. The modified "as-treated" patient population (mITT group) included 465 recipients of allogeneic hematopoietic stem cell transplantation, of whom 45% had acute myeloid leukemia. Myeloablative conditioning was administered in 58% of all patients. Prophylaxis with the study drug was initiated immediately after hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 received itraconazole. The mean duration of prophylaxis in the mITT group was 96 days for voriconazole and 68 days for itraconazole. Efficacy rates and other secondary endpoints are presented in the table below.

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 probable or suspected invasive fungal infection by day 180	3 (1.3%)	5 (2.1%)	0.7% (–3.1%, 1.6%)	0.5390
Development of probable or suspected invasive fungal infection by day 100	2 (0.9%)	4 (1.7%)	0.8% (–2.8%, 1.3%)	0.4589
Development of probable or suspected invasive fungal infection during study drug administration	0	3 (1.2%)	1.2% (–2.6%, 0.2%)	0.0813

* Primary efficacy endpoint of the study.

** Differences in proportions, with 95% CI and P-values, adjusted for randomization.

Incidence of invasive fungal infection by day 180 and the primary efficacy endpoint of the study, i.e., "efficacy by day 180," in patients with acute myeloid leukemia and conditioning are presented in the table below.

Acute Myeloid Leukemia

Endpoint	Voriconazole (N=98)	Itraconazole (N=109)	Difference in proportions and 95% confidence interval (CI)
Incidence of invasive fungal infection – day 180	1 (1.0%)	2 (1.8%)	0.8% (–4.0%, 2.4%) **
Effectiveness at 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.

Myeloablative conditioning regimen

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

* Primary endpoint of the study.

** Non-inferiority demonstrated with a 5% margin.

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

Secondary prophylaxis of invasive fungal infection – efficacy in hematopoietic stem cell transplant recipients with prior documented or suspected invasive fungal infection. Voriconazole was studied as a secondary prophylactic agent in an open-label, non-comparative, multicenter study in adult recipients of allogeneic hematopoietic stem cell transplantation with prior documented or suspected invasive fungal infection. The primary endpoint was the incidence of documented 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.

Documented 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 Scedosporium infection (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 at 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. Fifty-three pediatric patients aged 2 to 18 years received voriconazole treatment in two prospective, open-label, non-comparative, multicenter clinical studies. One study included 31 patients with possible, proven, or probable invasive aspergillosis, of whom 14 had proven or probable invasive aspergillosis. These patients were included in the efficacy analysis of the modified intent-to-treat (mITT) population who received treatment. The second study included 22 patients with invasive candidiasis, including candidemia and esophageal candidiasis, who required primary or salvage therapy. Of these patients, 17 were included in the efficacy analysis of the mITT population who received treatment. 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, single-dose study in healthy volunteers was conducted to evaluate the effect of investigational agents on the QTc interval. Three doses of oral voriconazole and oral ketoconazole were administered during the study. The placebo-corrected mean maximum QTc prolongation from baseline was 5.1, 4.8, and 8.2 ms after administration of 800, 1200, and 1600 mg of voriconazole, respectively, and 7.0 ms after administration of 800 mg of ketoconazole. No study participant had a QTc prolongation of ≥ 60 ms from baseline. No participant exceeded the potentially clinically significant threshold of 500 ms.

Pharmacokinetics.

General pharmacokinetic characteristics. The pharmacokinetics of voriconazole 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—namely, 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. As the dose increases, 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. When oral or intravenous loading doses of voriconazole are administered, plasma concentrations close to steady-state are achieved within the first 24 hours of therapy. Without a loading dose regimen, with repeated administration of voriconazole twice daily, accumulation to steady-state plasma concentrations occurs by day 6 in most patients.

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with Cmax reached 1–2 hours post-dose. The absolute bioavailability of voriconazole after oral administration is 96%. Repeated administration of voriconazole with a high-fat meal reduces Cmax and AUCτ by 34% and 24%, respectively. Gastric pH changes do not affect voriconazole absorption.

Distribution. The volume of distribution at steady state for voriconazole 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 quantities in all cerebrospinal fluid samples obtained from 8 patients within a compassionate-use program.

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

In vivo studies have demonstrated 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 of this drug. Among Caucasian and Negroid populations, the proportion of slow metabolizers is 3–5%. Studies conducted in Caucasian and Japanese healthy volunteers have shown that in "slow metabolizers" of voriconazole, drug exposure (AUCτ) 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 the comparator group of homozygous "rapid metabolizers."

The main metabolite of voriconazole is N-oxide, which accounts for 72% of the total circulating radiolabeled metabolites 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 radioactive substances were eliminated within the first 96 hours after both intravenous and oral administration.

The half-life of voriconazole depends on the dose and is approximately 6 hours after an oral 200 mg dose. Due to non-linear pharmacokinetics, half-life 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 levels in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18–45 years). In the same study, no statistically significant differences in these parameters were observed between healthy elderly men and women (≥ 65 years). In the clinical program, dose adjustment was not performed based on gender. 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 multiple-dose oral study, Cmax and AUCτ levels 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 levels were observed between healthy elderly women (≥ 65 years) and healthy young women (18–45 years).

Dose adjustment was not performed based on age in the studies. A relationship between plasma concentrations and age was observed. Safety profiles of voriconazole in young 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 doses of 3, 4, 6, 7, and 8 mg/kg twice daily intravenously 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 pharmacokinetic study in children. This patient population showed greater individual variability compared to adults.

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

The higher maintenance intravenous 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 to voriconazole in most older children was comparable to that in adults at the same dosing regimen. However, in some older children with low body weight, lower voriconazole exposure was observed compared to adults. Metabolism of voriconazole in such patients appears to be 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 moderate to severe renal impairment (serum creatinine < 2.5 mg/dL), accumulation of sodium sulfobutylether-β-cyclodextrin occurs (see sections "Dosage and administration" and "Special warnings and precautions for use").

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

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

Clinical characteristics.

Indications.

Prophylaxis of invasive fungal infections in patients undergoing allogeneic hematopoietic stem cell transplantation who are at high risk for such complications.

Voriconazole is indicated in adults and children aged 2 years and older for the treatment of:

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

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

Contraindications.

• Hypersensitivity to voriconazole or to any excipient of the medicinal product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, or quinidine, as increased plasma concentrations of these drugs may lead to QTc interval prolongation and, rarely, to the development of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with rifampicin, carbamazepine, and phenobarbital, as these medicinal products can significantly reduce voriconazole plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of standard doses of voriconazole with efavirenz at a dose of 400 mg or higher per day, as efavirenz at these doses significantly reduces voriconazole plasma concentrations in healthy volunteers. Voriconazole also significantly increases efavirenz plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"; for use of lower efavirenz doses, see section "Special precautions for use").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily), as such ritonavir doses lead to a significant reduction in voriconazole plasma concentrations in healthy volunteers (for use of 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 result in ergotism (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with St. John's wort (Hypericum perforatum) preparations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with venetoclax at initiation 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 below).

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

Voriconazole should be used with caution in patients receiving other medicinal products that prolong the QTc interval. In cases where voriconazole may also increase plasma concentrations of substances metabolized by CYP3A4 (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 1. The direction of arrows for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio.

Symbols and abbreviations used in the table and their meanings: ↔ – within 80–125%; ↑ – above 80–125%; ↓ – below 80–125%; * – bidirectional interaction; AUCτ – area under the 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 the table 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.

Table 1

Medicinal product (mechanism of interaction)	Interaction Mean geometric change, %	Recommendations for concomitant use
Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine (CYP3A4 substrates)	Although appropriate studies have not been conducted, increased plasma concentrations of these substances may lead to QTc interval prolongation and rarely to the development of ventricular tachycardia of the "torsades de pointes" type	Contraindicated (see section "Contraindications")
Carbamazepine and long-acting barbiturates, e.g. phenobarbital, mefobarbital (potent CYP450 inducers)	Despite the lack of appropriate studies, carbamazepine and long-acting barbiturates are expected 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 concomitantly with 400 mg voriconazole twice daily*	efavirenz Cmax ↑ 38 % efavirenz AUCτ ↑ 44 % voriconazole Cmax ↓ 61 % voriconazole AUCτ ↓ 77 % Compared to 600 mg efavirenz once daily: efavirenz Cmax ↔ efavirenz AUCτ ↑ 17 % Compared to 200 mg voriconazole twice daily: voriconazole Cmax ↑ 23 % voriconazole AUCτ ↓ 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, the initial dose of efavirenz should be resumed (see section "Dosage and administration" and "Special instructions")
Ergot alkaloids, e.g. ergotamine and dihydroergotamine (CYP3A4 substrates)	Although appropriate studies have not been conducted, voriconazole is known to increase plasma concentrations of ergot alkaloids and may lead to ergotism	Contraindicated (see section "Contraindications")
Rifabutin (potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitantly with voriconazole 350 mg twice daily*) 300 mg once daily (concomitantly with voriconazole 400 mg twice daily*)	voriconazole Cmax ↓ 69 % voriconazole AUCτ ↓ 78 % Compared to 200 mg voriconazole twice daily: voriconazole Cmax ↓ 4 % voriconazole AUCτ ↓ 32 % rifabutin Cmax ↑ 195 % rifabutin AUCτ ↑ 331 % Compared to 200 mg voriconazole twice daily: voriconazole Cmax ↑ 104 % voriconazole AUCτ ↑ 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 for patients with body weight below 40 kg) (see section "Dosage and administration"). When rifabutin and voriconazole are used concomitantly, careful monitoring of complete blood count and rifabutin-related adverse reactions (such as uveitis) is recommended
Rifampicin (600 mg once daily) (potent CYP450 inducer)	voriconazole Cmax ↓ 93 % voriconazole AUCτ ↓ 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)*	ritonavir Cmax and AUCτ ↔ voriconazole Cmax ↓ 66 % voriconazole AUCτ ↓ 82 % ritonavir Cmax ↓ 25 % ritonavir AUCτ ↓ 13 % voriconazole Cmax ↓ 24 % voriconazole AUCτ ↓ 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 use with single 400 mg voriconazole dose)	In an independent published study, voriconazole AUC0-∞ ↓ 59 %	Contraindicated (see section "Contraindications")
Venetoclax (CYP3A substrate)	Although appropriate studies have not been conducted, voriconazole is known to cause a significant increase in venetoclax plasma concentration	Concomitant use of voriconazole is contraindicated during initiation and dose-titration phase of venetoclax (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.
Everolimus (CYP3A4 substrate, P-glycoprotein substrate)	Although appropriate studies have not been conducted, voriconazole is known to cause a significant increase in everolimus plasma concentration	Concomitant use of everolimus and voriconazole is not recommended, as voriconazole may cause a significant increase in everolimus concentration (see section "Special instructions")
Naloxegol (CYP3A4 substrate)	Use of voriconazole has not been studied, but it is likely to significantly increase plasma concentrations of naloxegol	Concomitant use of voriconazole and naloxegol is not recommended due to insufficient data to provide clear dosing guidance for naloxegol in this situation (see section "Special instructions")
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor), 200 mg once daily	voriconazole Cmax ↑ 57 % voriconazole AUCτ ↑ 79 % fluconazole Cmax – n/s fluconazole AUCτ – n/s	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 immediately after fluconazole, monitoring for voriconazole-related adverse reactions is recommended
Phenytoin (CYP2C9 substrate and potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitantly with 400 mg voriconazole twice daily)*	voriconazole Cmax ↓ 49 % voriconazole AUCτ ↓ 69 % phenytoin Cmax ↑ 67 % phenytoin AUCτ ↑ 81 % Compared to 200 mg voriconazole twice daily: voriconazole Cmax ↑ 34 % voriconazole AUCτ ↑ 39 %	Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk. When phenytoin and voriconazole are used concomitantly, careful monitoring of phenytoin plasma 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 for patients with body weight below 40 kg) (see section "Dosage and administration")
Letermovir (CYP2C9 and CYP2C19 inducer)	voriconazole Cmax ↓ 39 % voriconazole AUC0-12 ↓ 44 % voriconazole C12 ↓ 51 %	If concomitant use of voriconazole and letermovir cannot be avoided, monitoring for possible loss of voriconazole efficacy is required
Anticoagulants Warfarin (CYP2C9 substrate) (single 30 mg warfarin dose concomitantly with 300 mg voriconazole twice daily) Other oral coumarins, such as phenprocoumon, acenocoumarol (CYP2C9 and CYP3A4 substrates)	Maximum prothrombin time increased approximately twofold Although appropriate studies have not been conducted, voriconazole is known to increase plasma concentrations of coumarins and thus may prolong prothrombin time	Prothrombin time and other appropriate coagulation parameters should be carefully monitored and anticoagulant doses adjusted accordingly
Ivacaftor (CYP3A4 substrate)	Interaction between voriconazole and ivacaftor has not been studied, but increased plasma concentration of ivacaftor is likely, which may increase 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 expected to increase plasma concentrations of benzodiazepines metabolized by CYP3A4 and prolong sedative effects	Dose reduction of benzodiazepines should be considered
Tolvaptan (CYP3A substrate)	Use of voriconazole has not been studied, but it is likely to significantly increase tolvaptan plasma concentrations	If concomitant use of voriconazole with tolvaptan is necessary, the dose of the latter should be reduced
Immunosuppressants (CYP3A4 substrates) Sirolimus (single 2 mg dose) Cyclosporine (in stable renal transplant recipients on continuous cyclosporine therapy) Tacrolimus (single 0.1 mg/kg dose)	In an independent published study: sirolimus Cmax ↑ 6.6-fold, sirolimus AUC0-∞ ↑ 11-fold cyclosporine Cmax ↑ 13 % cyclosporine AUCτ ↑ 70 % tacrolimus Cmax ↑ 117 % tacrolimus AUCt ↑ 221 %	Concomitant use contraindicated (see section "Contraindications") At initiation of voriconazole therapy in patients already receiving cyclosporine, cyclosporine dose should be reduced by half and cyclosporine levels should be closely monitored. Elevated cyclosporine levels are associated with nephrotoxic effects. After discontinuation of voriconazole, cyclosporine levels should be closely monitored and dose increased if necessary At initiation of voriconazole therapy in patients already receiving tacrolimus, tacrolimus dose should be reduced to one-third of the initial dose and tacrolimus levels closely monitored. 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 (single 10 mg dose)	In an independent published study: oxycodone Cmax ↑ 1.7-fold oxycodone AUC0-∞ ↑ 3.6-fold	Dose reduction of oxycodone and other CYP3A4-metabolized long-acting opioids (e.g. hydrocodone) should be considered. Close monitoring for opioid-related adverse reactions is recommended
Methadone (CYP3A4 substrate) (32-100 mg once daily)	R-methadone (active) Cmax ↑ 31 % R-methadone (active) AUCτ ↑ 47 % S-methadone Cmax ↑ 65 % S-methadone AUCτ ↑ 103 %	Continuous monitoring for adverse reactions and toxic effects associated with elevated methadone plasma concentrations, including QT interval prolongation, is recommended. Dose reduction of methadone may be necessary
Nonsteroidal anti-inflammatory drugs (NSAIDs) (CYP2C9 substrates) Ibuprofen (single 400 mg dose) Diclofenac (single 50 mg dose)	S-ibuprofen Cmax ↑ 20 % S-ibuprofen AUC0-∞ ↑ 100 % diclofenac Cmax ↑ 114 % diclofenac AUC0-∞ ↑ 78 %	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*	omeprazole Cmax ↑ 116 % omeprazole AUCτ ↑ 280 % voriconazole Cmax ↑ 15 % voriconazole AUCτ ↑ 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. At initiation of voriconazole therapy in patients already receiving omeprazole (40 mg or higher), omeprazole dose should be reduced by half
Oral contraceptives (CYP3A4 substrates, CYP2C19 inhibitors) Norethisterone/ethinylestradiol (1 mg/0.035 mg once daily)	ethinylestradiol Cmax ↑ 36 % ethinylestradiol AUCτ ↑ 61 % norethisterone Cmax ↑ 15 % norethisterone AUCτ ↑ 53 % voriconazole Cmax ↑ 14 % voriconazole AUCτ ↑ 46 %	Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended
Short-acting opioids (CYP3A4 substrates) Alfentanil (single 20 μg/kg dose, concomitantly with naloxone) Fentanyl (single 5 μg/kg dose)	In an independent published study: alfentanil AUC0-∞ ↑ 6-fold In an independent published study: fentanyl AUC0-∞ ↑ 1.34-fold	Dose reduction of alfentanil, fentanyl and other structurally similar CYP3A4-metabolized short-acting opioids (e.g. sufentanil) should be considered. 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, which may lead to rhabdomyolysis	Dose reduction of statins should be considered
Sulfonylureas, e.g. tolbutamide, glipizide, glyburide (CYP2C9 substrates)	Although appropriate studies have not been conducted, voriconazole may increase plasma levels of sulfonylureas and thus cause hypoglycemia	Close monitoring of blood glucose levels is required. Dose reduction of sulfonylureas should be considered
Vinca alkaloids, e.g. vincristine and vinblastine (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole may increase plasma levels of vinca alkaloids and lead to neurotoxic effects	Dose reduction of vinca alkaloids should be considered
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 metabolism of HIV protease inhibitors, and voriconazole metabolism may be inhibited by HIV protease inhibitors	Close monitoring for signs of toxicity and/or lack of efficacy of these drugs is recommended. Dose adjustment may be appropriate
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 voriconazole may inhibit NNRTI metabolism. Based on studies of efavirenz effect on voriconazole, voriconazole metabolism may be induced by NNRTIs	Close monitoring for signs of toxicity and/or lack of efficacy of these drugs is recommended. Dose adjustment may be appropriate
Cimetidine (non-specific CYP450 inhibitor, increases gastric juice pH) (400 mg twice daily)	voriconazole Cmax ↑ 18 % voriconazole AUCτ ↑ 23 %	No dose adjustment required
Digoxin (P-glycoprotein substrate) (0.25 mg once daily)	digoxin Cmax ↔ digoxin AUCτ ↔	No dose adjustment required
Indinavir (CYP3A4 inhibitor and substrate) (800 mg three times daily)	voriconazole Cmax ↔ voriconazole AUCτ ↔ indinavir Cmax ↔ indinavir AUCτ ↔	No dose adjustment required
Macrolide antibiotics Erythromycin (CYP3A4 inhibitor) (1 g twice daily) Azithromycin (500 mg once daily)	voriconazole Cmax and AUCτ ↔ voriconazole Cmax and AUCτ ↔ Effect of voriconazole on erythromycin or azithromycin unknown	No dose adjustment required
Mycophenolic acid (UGT substrate) (1 g single dose)	mycophenolic acid Cmax and AUCt ↔	No dose adjustment required
Corticosteroids Prednisolone (CYP3A4 substrate) (60 mg single dose)	prednisolone Cmax ↑ 11 % prednisolone AUC0-∞ ↑ 34 %	No dose adjustment required Patients receiving long-term voriconazole and corticosteroid therapy (including inhaled corticosteroids, e.g. budesonide, and intranasal corticosteroids) should be closely monitored for adrenal insufficiency both during and after discontinuation of voriconazole (see section "Special instructions").
Ranitidine (increases gastric juice pH) (150 mg twice daily)	voriconazole Cmax and AUCτ ↔	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. Voriconazole should be used with caution in patients with hypersensitivity to other azoles.

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

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

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

Electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and corrected as necessary prior to and during voriconazole therapy. A study in healthy volunteers evaluating the effect of single doses of voriconazole up to 4 times the recommended daily dose on the QTc interval showed that in no subject did the QTc interval exceed the potentially clinically relevant threshold of 500 ms.

Infusion-related reactions.

Infusion-related reactions, primarily flushing and nausea, have been observed during intravenous administration of the drug. Depending on the severity of symptoms, discontinuation of therapy should be considered.

Hepatotoxicity. During clinical trials, serious hepatic reactions (including clinically apparent hepatitis, cholestasis, and fulminant hepatic failure, some fatal) were infrequently observed with voriconazole use. Hepatic reactions occurred primarily in patients with severe underlying conditions (particularly hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, have also been observed in patients without other identified risk factors. Liver function abnormalities were reversible and usually resolved upon discontinuation of therapy.

Liver function monitoring. Patients receiving voriconazole should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (particularly aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) at the start of treatment and at least once weekly during the first month of therapy. The duration of treatment should be as short as possible; however, if treatment continues based on a risk-benefit assessment, the frequency of monitoring may be reduced to

once monthly, provided liver test results remain stable.

If liver function tests show significant elevation, drug use should be discontinued, except in cases where a medical risk-benefit assessment justifies continued use.

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

Ocular side effects. Prolonged ocular adverse reactions have been reported, including blurred vision, optic neuritis, and optic disc edema.

Renal side effects. Acute renal failure has been reported in patients with severe underlying diseases receiving the drug. Patients receiving voriconazole may experience reduced renal function when concomitantly administered nephrotoxic drugs and/or with underlying conditions.

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, is recommended during treatment. Monitoring serum amylase or lipase levels may be necessary.

Serious skin reactions.

• Photosensitivity. Voriconazole use has additionally been associated with photosensitivity reactions such as freckles, lentigo, actinic keratosis, and pseudoporphyria. There is a potentially increased risk of skin reactions/toxicity with concomitant use of photosensitizing agents (e.g., methotrexate, etc.). All patients, including children, should avoid direct sunlight exposure, wear protective clothing, and use sunscreen with a high protection factor (SPF) during voriconazole therapy.
• Squamous cell carcinoma of the skin (including Bowen’s disease). Among patients who developed squamous cell carcinoma of the skin, some had prior history of photosensitivity reactions. In case of photosensitivity reactions, multidisciplinary physician consultations should be conducted, voriconazole therapy should be discontinued, consideration should be given to alternative antifungal agents, and the patient should be referred to a dermatologist. If voriconazole therapy continues, a dermatologist should systematically and regularly examine the patient for early detection and treatment of potential precancerous lesions. If precancerous skin lesions or squamous cell carcinoma are detected, voriconazole use must be discontinued (see section "Long-term therapy" below).
• Severe skin reactions. Cases of severe skin reactions 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 with voriconazole use. Patients with rash should be closely monitored, and voriconazole should be discontinued if signs of disease progression occur.

Long-term therapy. If prolonged use of the drug (treatment or prophylaxis) beyond 180 days (6 months) is necessary, a thorough benefit-risk assessment should be performed; physicians should consider limiting drug exposure.

Reports of the following serious adverse reactions have been associated with long-term voriconazole use.

Cases of squamous cell carcinoma of the skin have been reported in association with long-term voriconazole therapy.

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed in patients who underwent transplantation surgery. If a patient develops skeletal pain and radiological findings suggestive of periostitis, multidisciplinary physician consultations should be conducted and discontinuation of voriconazole should be considered.

Adrenal gland adverse reactions

Cases of adrenal insufficiency have been reported in patients receiving other azoles (e.g., ketoconazole), as well as reversible adrenal insufficiency in patients receiving voriconazole.

Patients receiving long-term voriconazole and corticosteroids (including inhaled corticosteroids such as budesonide and intranasal corticosteroids) should be closely monitored for adrenal cortical dysfunction both during and after discontinuation of voriconazole (see section "Interaction with other medicinal products and other forms of interaction").

Patients receiving long-term voriconazole and corticosteroids (including inhaled corticosteroids such as budesonide and intranasal corticosteroids) require monitoring of adrenal function both during and after discontinuation of voriconazole.

Cases of non-infectious periostitis with elevated fluoride and alkaline phosphatase levels have been observed in post-transplant patients. In the event of bone pain and radiographic findings characteristic of periostitis, after consultation with appropriate specialists, discontinuation of the drug should be considered.

Children. The safety and efficacy of the drug in children under 2 years of age have not been established. Voriconazole is recommended for use in children aged 2 years and older. 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 these patients.

• Serious skin reactions (including squamous cell carcinoma of the skin). The incidence of photosensitivity reactions is higher in children. If progression to squamous cell carcinoma of the skin is observed in patients in this group, enhanced protective measures against sunlight exposure should be implemented. Children with signs of photoaging, such as freckles or lentigo, should be under dermatological surveillance and avoid sun exposure even after discontinuation of the drug.

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

Phenytoin (CYP2C9 substrate and potent CYP450 inducer). Close monitoring of phenytoin levels is recommended when used concomitantly with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk.

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.

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.

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate). Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless the benefit of voriconazole use outweighs the risk.

Everolimus (CYP3A4 substrate, P-glycoprotein substrate). Concomitant use of everolimus and voriconazole is not recommended, as voriconazole is expected to cause a significant increase in everolimus concentration. Currently, there is insufficient information on dosage adjustment.

Naloxegol (CYP3A4 substrate)

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

Methadone (CYP3A4 substrate). Close monitoring for adverse reactions and signs of methadone toxicity (including QTc 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.

Short-acting opioids (CYP3A4 substrates). When short-acting opioids and voriconazole are used concomitantly, consider reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil). Monitoring for opioid-related adverse reactions (including prolonged respiratory function monitoring) may be necessary, as the half-life of alfentanil is prolonged 4-fold with concomitant voriconazole use, and published data from one study indicate that concomitant use of fentanyl and voriconazole led to increased mean AUC0-∞ of fentanyl.

Long-acting opioids (CYP3A4 substrates). When long-acting opioids and voriconazole are used concomitantly, consider reducing the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone). Monitoring for opioid-related adverse reactions may be necessary.

Fluconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4). 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 eliminate this effect. Monitoring for voriconazole-related adverse reactions is recommended when voriconazole is used immediately after fluconazole.

Sodium content. Each vial contains 88.74 mg of sodium, which should be considered when administering the drug to patients requiring sodium intake control.

Cyclodextrins. The powder for solution for infusion contains cyclodextrins (3200 mg cyclodextrins per vial, equivalent to 160 mg/mL when reconstituted in 20 mL), which may affect the properties (e.g., toxicity) of the active substance and other medicinal products.

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

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.

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

Women of childbearing potential who may become pregnant should use effective contraception during treatment with this drug.

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

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 or 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 starting treatment and during the use of the drug, monitoring for electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia is required; if necessary, appropriate correction should be performed.

The recommended maximum infusion rate is 3 mg/kg/hour, administered over 1–3 hours.

Treatment.

Adults. To achieve plasma concentrations close to steady-state levels on the first day of treatment, therapy with the drug should be initiated using an appropriate regimen of loading doses administered either orally or intravenously. Due to the high bioavailability of the drug after oral administration (96%), the route of administration may be switched from intravenous to oral, or vice versa, when clinically indicated.

Detailed dosage recommendations are provided in Table 2.

Table 2

Dosing regimen	Intravenous	Oral
		Patients with body weight 40 kg or more*	Patients with body weight less than 40 kg*
Loading doses (during 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 the start of treatment)	4 mg/kg twice daily	200 mg twice daily	100 mg twice daily

• Including patients aged 15 years and older.

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

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 there is an inadequate response to treatment, 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.

Dose selection when co-administered with other agents.

Rifabutin or phenytoin may be co-administered with voriconazole provided that the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily.

Efavirenz may be co-administered with voriconazole provided that the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the dose of efavirenz is reduced by 50%, i.e., to 300 mg once daily. After discontinuation of voriconazole, the initial dose of efavirenz should be resumed.

Elderly patients. There is no need for dose adjustment in elderly patients.

Patients with renal impairment.

In patients with moderate to severe renal impairment (creatinine clearance < 50 ml/min), accumulation of sodium sulfobutyl ether β-cyclodextrin occurs. Voriconazole should be administered orally to these patients, except when the benefit of intravenous voriconazole outweighs the risks. In such patients, careful monitoring of serum creatinine levels is required. If serum creatinine increases, consideration should be given to switching the route of administration of voriconazole to oral.

The clearance of voriconazole during hemodialysis is 121 ml/min. The amount of voriconazole removed during a 4-hour hemodialysis session is negligible; therefore, dose adjustment is not necessary.

The clearance of sodium sulfobutyl ether β-cyclodextrin during hemodialysis is 55 ml/min.

Patients with 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.

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

Safety data on voriconazole use in patients with abnormal liver function test results (AST, ALT, alkaline phosphatase, and total bilirubin more than 5 times the upper limit of normal) are limited.

The use of the drug 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 hepatic impairment.

Method of administration.

Prior to intravenous infusion, the drug must be reconstituted and diluted. The drug is not intended for bolus injection.

To obtain 20 ml of a clear concentrate containing 10 mg/ml of voriconazole, the powder should be dissolved in 19 ml of water for injection or in 19 ml of 9 mg/ml (0.9%) sodium chloride infusion solution. Do not use the vial if the diluent does not get drawn into the vial by vacuum force. It is recommended to use a standard (non-automated) 20 ml syringe to ensure accurate addition of 19 ml of water for injection or 9 mg/ml (0.9%) sodium chloride infusion solution.

The drug is intended for single use only; only clear solutions free from mechanical particulates should be used.

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

Required volumes of drug concentrate (10 mg/ml).

Table 3

Body weight (kg)	Volume of concentrate (10 mg/mL) required to achieve:
	3 mg/kg dose (number of vials)	4 mg/kg dose (number of vials)	6 mg/kg dose (number of vials)	8 mg/kg dose (number of vials)	9 mg/kg dose (number of vials)
10		4 mL (1)		8 mL (1)	9 mL (1)
15		6 mL (1)		12 mL (1)	13.5 mL (1)
20		8 mL (1)		16 mL (1)	18 mL (1)
25		10 mL (1)		20 mL (1)	22.5 mL (1)
30	9 mL (1)	12 mL (1)	18 mL (1)	24 mL (2)	27 mL (2)
35	10.5 mL (1)	14 mL (1)	21 mL (2)	28 mL (2)	31.5 mL (2)
40	12 mL (1)	16 mL (1)	24 mL (2)	32 mL (2)	36 mL (2)
45	13.5 mL (1)	18 mL (1)	27 mL (2)	36 mL (2)	40.5 mL (2)
50	15 mL (1)	20 mL (1)	30 mL (2)	40 mL (2)	45 mL (2)
55	16.5 mL (1)	22 mL (2)	33 mL (2)	44 mL (3)	49.5 mL (3)
60	18 mL (1)	24 mL (2)	36 mL (2)	48 mL (3)	54 mL (3)
65	19.5 mL (1)	26 mL (2)	39 mL (2)	52 mL (3)	58.5 mL (3)
70	21 mL (2)	28 mL (2)	42 mL (3)
75	22.5 mL (2)	30 mL (2)	45 mL (3)
80	24 mL (2)	32 mL (2)	48 mL (3)
85	25.5 mL (2)	34 mL (2)	51 mL (3)
90	27 mL (2)	36 mL (2)	54 mL (3)
95	28.5 mL (2)	38 mL (2)	57 mL (3)
100	30 mL (2)	40 mL (2)	60 mL (3)

The reconstituted solution may be diluted with the following solutions:

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

Compatibility of voriconazole with other solvents is unknown.

Any unused solution leftovers should be disposed of according to local requirements.

Information on the use of the medicinal product for prophylaxis is provided below.

Prophylaxis in adults and children

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

Dosing.

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. See Tables 2 and 4.

Duration of prophylaxis.

The safety and efficacy of using voriconazole for longer than 180 days have not been adequately studied in clinical trials.

The use of voriconazole as prophylaxis for longer than 180 days (6 months) requires careful assessment of the benefit-risk balance.

Dose adjustment (applies to both treatment and prophylaxis).

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

Children.

The medicinal product can be 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 4

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 oral administration should only be considered after achieving significant clinical improvement. It should be noted that an intravenous dose of 8 mg/kg provides voriconazole exposure approximately twice that achieved with an oral dose of 9 mg/kg. Not for bolus injection.

For children aged 12–14 years with body weight ≥ 50 kg and for children aged 15–17 years regardless of body weight, the same voriconazole doses as for adults should be used.

Dose adjustment for pediatric patients aged 2–12 years and for children 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. If the patient does not tolerate the treatment, the intravenous dose should be reduced by 1 mg/kg.

The use of the drug in pediatric patients aged 2–12 years with renal or hepatic insufficiency has not been studied.

Overdose.

Three cases of accidental overdose have been reported. All three cases occurred in children who received intravenous doses up to 5 times higher than the recommended dose. The only adverse reaction reported was photophobia lasting 10 minutes. There is no known antidote for voriconazole.

The clearance of voriconazole during hemodialysis is 121 ml/min. The clearance of sodium
β-cyclodextrin sulfobutyl ether during hemodialysis is 55 ml/min.

In cases of overdose, hemodialysis may facilitate the elimination of voriconazole and sodium
β-cyclodextrin sulfobutyl ether 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, pyrexia, 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. Safety data analysis revealed no clinically significant differences based on age, race, or gender.

Adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are presented in order of decreasing severity.

Infections and infestations: common – sinusitis; uncommon – pseudomembranous colitis.

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

Common: squamous cell carcinoma (including 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.

Nervous system disorders: very common – headache; common – seizures, tremor, paraesthesia, hypertonia³, somnolence, syncope, dizziness; uncommon – brain edema, encephalopathy⁴, extrapyramidal symptoms⁵, peripheral neuropathy, ataxia, hypaesthesia, dysgeusia; rare – nystagmus, hepatic encephalopathy, Guillain–Barré syndrome.

Eye disorders: very common – visual disturbances⁶ (including blurred vision, chromopsia, and photophobia); common – retinal hemorrhage; uncommon – oculogyric crisis, optic nerve disorders⁷ (including optic neuritis), optic disc edema⁸, scleritis, blepharitis, diplopia; rare – optic atrophy, corneal opacity.

Ear and labyrinth disorders: uncommon – hearing impairment, vertigo, tinnitus.

Cardiac disorders: common – supraventricular arrhythmia, tachycardia, bradycardia, ventricular fibrillation, hypotension, phlebitis; uncommon – ventricular extrasystoles, supraventricular tachycardia, ventricular tachycardia, QT interval prolongation on electrocardiogram, thrombophlebitis, lymphangitis; rare – torsades de pointes ventricular tachycardia, complete atrioventricular block, bundle branch block, nodal rhythm, thrombophlebitis.

Respiratory, thoracic and mediastinal disorders: very common – respiratory disorders⁹; common – acute respiratory distress syndrome, pulmonary edema.

Gastrointestinal disorders: very common – abdominal pain, nausea, vomiting, diarrhea; common – dyspepsia, constipation, cheilitis, gingivitis; uncommon – pancreatitis, duodenitis, glossitis, tongue swelling, gastroenteritis, peritonitis.

Hepatobiliary disorders: very common – abnormal liver function tests (including AST, ALT, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, bilirubin); common – jaundice, cholestatic jaundice, hepatitis¹⁰; uncommon – hepatic failure, hepatomegaly, cholecystitis, cholelithiasis.

Skin and subcutaneous tissue disorders: very common – rash; common – exfoliative dermatitis, maculopapular rash, pruritus, alopecia, erythema, photosensitivity; uncommon – Stevens–Johnson syndrome, erythema multiforme, angioedema, psoriasis, urticaria, allergic dermatitis, macular rash, papular rash, purpura, eczema; rare – toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), 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, periostitis*.

Renal and urinary disorders: common – acute renal failure, hematuria; uncommon – acute tubular necrosis, proteinuria, albuminuria, nephritis.

General disorders and administration site conditions: very common – pyrexia; common – chest pain, facial edema¹¹, asthenia, chills; uncommon – influenza-like illness, infusion site reactions.

Investigations: common – increased blood creatinine; uncommon – QTc interval prolongation on electrocardiogram, increased blood urea, increased blood cholesterol.

* Adverse reactions identified post-marketing.

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 "Visual disturbances" section under "Adverse reactions".

7 Post-marketing reports of prolonged optic neuritis (see "Special warnings and precautions for use").

8 See "Special warnings and precautions for use".

9 Includes dyspnea and exertional dyspnea.

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

11 Includes periorbital edema, lip swelling, and oral cavity swelling.

Description of selected adverse reactions

Eye disorders. Visual disturbances (including blurred vision, photophobia, chloropsia, chromopsia, color blindness, cyanopsia, visual disturbances with rainbow-colored halos, night blindness, oscillopsia, photopsia, flickering scotoma, reduced visual acuity, visual brightness, visual field defects, floaters, and xanthopsia) were very commonly observed during clinical trials and were associated with voriconazole use. These visual disturbances were transient and fully reversible, typically resolving spontaneously within 60 minutes; no clinically significant long-term visual effects were observed. Symptoms tended to diminish with repeated dosing. Visual disturbances were generally mild, rarely led to drug discontinuation, and were not associated with persistent sequelae. Visual disturbances may be related to high plasma concentrations and/or drug doses.

The mechanism of visual disturbances is unknown, although it is likely that the drug 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 voriconazole discontinuation.

Post-marketing reports have described prolonged ocular adverse reactions (see "Special warnings and precautions for use").

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

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

Cases of serious photosensitivity reactions, including freckles, lentigo, and actinic keratosis, have been reported, particularly with prolonged drug use (see "Special warnings and precautions for use").

Cases of cutaneous squamous cell carcinoma have been reported in patients receiving long-term Voriconazole Zentiva; the mechanism of this phenomenon is not established (see "Special warnings and precautions for use").

Liver function tests. During the clinical development 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 treatment or prophylaxis. Abnormal liver function tests may be associated with high plasma concentrations and/or drug doses. Most abnormalities resolved during continued treatment without dose adjustment or after dose modification, including drug discontinuation.

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

Infusion-related reactions. Anaphylactoid-type reactions, including flushing, hot flushes, increased sweating, tachycardia, chest tightness, dyspnea, syncope, nausea, pruritus, and rash, have been reported. Symptoms occurred immediately after the start of infusion (see "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, complete discontinuation of voriconazole due to adverse reactions occurred in 39.3% of patients compared to 39.6% in the itraconazole group. Treatment-related hepatic 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) or treatment (105) in clinical trials. Safety was also assessed in 158 children aged 2 to 12 years in compassionate-use programs. Overall, the safety profile of voriconazole in children was similar to that in adults. However, a higher incidence of elevated liver enzymes was observed in children compared to adults (transaminase elevation occurred in 14.2% of children versus 5.3% of adults), reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the frequency of skin reactions (particularly erythema) may be somewhat higher in children than in adults. In 22 patients under 2 years of age receiving voriconazole in compassionate-use programs, the following adverse reactions, for which a causal relationship with voriconazole could not be excluded, 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.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legal requirements.

Shelf life. 3 years.

Storage conditions.

No special storage requirements.

Chemical and physical stability of the reconstituted and diluted product has been demonstrated for 72 hours at room temperature and at 2–8°C.

From a microbiological standpoint (after dilution and reconstitution), the product should be used immediately. If not used immediately, storage times should not exceed 24 hours at 2°C–8°C (in a refrigerator), unless reconstitution and dilution were performed under controlled and validated aseptic conditions.

Incompatibilities.

Infusion of the medicinal product must not be administered simultaneously with other intravenous agents using the same infusion line or cannula. After completion of voriconazole infusion, the infusion line may be used for administration of other intravenous medicinal products.

Blood products and short-term infusions of concentrated electrolyte solutions: electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to initiation of voriconazole therapy. Voriconazole 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 infusion lines.

Total parenteral nutrition (TPN): total parenteral nutrition should not be discontinued during administration of the medicinal product but should be administered through a separate infusion line. When administered via a multi-lumen catheter, TPN should be given through a separate port, not through the port used for voriconazole infusion. The medicinal product must not be diluted with 4.2% sodium bicarbonate solution for infusion. 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 "Posology and method of administration".

Packaging. 200 mg of powder in a type I glass vial, 25 ml volume, stoppered with a grey rubber stopper and sealed with an aluminum cap and a red plastic cap. One vial per cardboard carton.

Prescription category. Prescription only.

Manufacturers.

Anfarm Ellas S.A.

FARMATEN S.A.

Manufacturers' addresses and locations of operations.

61 km NAT.RD.AFINI-LAMIA, Schimatari Viotias, 32009, Greece.

6, Dervenakion, Pallini Attiki, 15351, Greece.

In case of adverse events, adverse reactions, or lack of therapeutic effect, please contact: ZENTIVA UKRAINE LLC, 5 "I" Brovarskyi Avenue, Kyiv, 02660, Ukraine; tel./fax: +38 044 517-75-00; email: [email protected]