Vorikocid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORICOCID (VORICOCID)

Composition:

Active substance: voriconazole;

1 vial contains 200 mg of voriconazole;

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

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: white or almost white lyophilized powder.

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 enzymes, which is a key step in ergosterol biosynthesis. Accumulation of 14α-methylsterols 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.

During 10 therapeutic studies, the median steady-state and maximum plasma concentrations in 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 correlation between mean, maximum, or minimum plasma concentrations of voriconazole and efficacy was not established during therapeutic studies, nor was such a correlation demonstrated in prophylactic studies. Pharmacokinetic/pharmacodynamic analysis of data from clinical trials identified a positive association between plasma concentrations of voriconazole and elevations in liver function tests and 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 exhibits fungicidal activity against all tested Asperg游戏副本 species. In addition, voriconazole demonstrates in vitro fungicidal activity against emerging fungal pathogens, including Scedosporium and Fusarium species, which often show 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 shown to respond 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, and Cladophialophora species, as well as Histoplasma capsulatum, with inhibition of most isolates occurring at voriconazole concentrations of 0.05–2 µg/mL. In vitro activity of voriconazole has also been demonstrated against various Curvularia and Sporothrix species, although the clinical significance of this activity remains to be determined.

Control points. Prior to initiating therapy, fungal cultures and other appropriate laboratory tests (serological, histopathological) should be obtained to isolate and identify the causative microorganisms. Therapy may be initiated before culture and laboratory results are available; however, once results become available, 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 typically have voriconazole MICs below 1 mg/L. However, in vitro activity of voriconazole against Candida species is not uniform. In particular, for C. glabrata, MICs of voriconazole are 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 susceptibility testing results for fungal pathogens are available, MIC data may be interpreted using susceptibility breakpoint criteria established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1

EUCAST susceptibility breakpoints

Clinical experience. Within this section, a favorable outcome of voriconazole use was 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 amphotericin B as first-line therapy 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 positive outcomes with voriconazole in patients with poor-prognosis risk factors, including graft-versus-host disease, 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, malignant tumors, and AIDS.

Candidemia in non-neutropenic patients. The efficacy of voriconazole compared to a regimen of amphotericin B followed by fluconazole as first-line therapy for candidemia was demonstrated in an open-label comparative study. A total of 370 non-neutropenic patients (aged 12 years and older) with documented candidemia were enrolled, of whom 248 received voriconazole. 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. According to the primary analysis, favorable response to treatment, as assessed by the blinded Data Monitoring 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 for 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 Data Monitoring Committee assessments 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 outcome as assessed by investigators at each of these evaluable time points are presented in Table 2.

Table 2

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). Among patients infected with fluconazole-resistant strains not belonging to Candida albicans, 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). Clinical efficacy data were supported by limited data on pathogen susceptibility testing to voriconazole.

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 (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 sinus infection, and 3 had disseminated infection. Another 4 patients with fusariosis were infected with multiple pathogens, and 2 of these patients showed a favorable treatment outcome. Most patients who received voriconazole for the treatment of the aforementioned 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 post-transplantation (uninterrupted for >14 days) and survival without confirmed or suspected invasive fungal infection within 180 days post-transplantation. The modified "intention-to-treat" (ITT) population included 465 recipients of allogeneic hematopoietic stem cell transplantation, of whom 45% had acute myeloid leukemia. Of all patients, 58% received a myeloablative conditioning regimen. Prophylaxis with the study drug was initiated immediately after hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 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

* Primary efficacy endpoint of the study.

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

Rates of invasive fungal infection by day 180 and the primary efficacy endpoint, i.e., "efficacy by day 180," in patients with acute myeloid leukemia and myeloablative conditioning regimen are presented in Table 4.

Table 4

Acute myeloid leukemia.

• Primary endpoint of the study.

** Non-inferior efficacy demonstrated with a margin of 5%.

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

Table 5

Myeloablative conditioning regimen.

* Primary endpoint of the study.

** Non-inferiority demonstrated 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 prior proven 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 prior proven or suspected invasive fungal infection. The primary endpoint was the incidence of proven 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 prophylaxis with the investigational drug in the ITT population was 95.5 days. Proven 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 at 1 year was 70.0% (28/40).

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

Children. Fifty-three 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 analyses of the modified intent-to-treat 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 analyses of the modified intent-to-treat 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 70.0% (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 was conducted in healthy volunteers to evaluate the effect of investigational agents on the QTc interval. Three doses of voriconazole and ketoconazole were administered orally during the study. The placebo-corrected mean maximum QTc prolongation from baseline was 5.1 ms, 4.8 ms, 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 study participant had a QTc prolongation ≥ 60 ms from baseline. No participant 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 voriconazole at doses 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 pharmacokinetic parameters evaluated (rate and uniformity of absorption, accumulation, and non-linear pharmacokinetics) were similar to those in healthy volunteers.

Voriconazole pharmacokinetics are non-linear due to its extensive metabolism. As the dose increases, the increase in exposure is greater than proportional. It is estimated that increasing the oral dose of voriconazole from 200 mg to 300 mg twice daily results in an average 2.5-fold increase in exposure (AUCτ). An oral loading dose of 200 mg (or 100 mg for patients with body weight below 40 kg) achieves exposure equivalent to 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 are administered, plasma concentrations of voriconazole 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 and attainment of steady-state plasma concentrations occur by day 6 in most patients.

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with maximum concentration (Cmax) reached within 1–2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is 96%. When voriconazole is administered repeatedly with a high-fat meal, Cmax and AUCτ are reduced by 34% and 24%, respectively. Gastric pH changes do not affect voriconazole absorption.

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

Metabolism. In vitro studies have 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 of voriconazole. Among Caucasian and Negroid populations, the proportion of slow metabolizers is 3–5%. Studies conducted in healthy volunteers of Caucasian race and Japanese demonstrated that in "slow metabolizers" of voriconazole, AUCτ is on average 4 times higher than in the comparison group of homozygous "rapid metabolizers" of voriconazole. Heterozygous "rapid metabolizers" of voriconazole have on average 2 times higher drug exposure than the comparison group of homozygous "rapid metabolizers". The main metabolite of voriconazole is N-oxide, which accounts for 72% of all radiolabeled metabolites circulating in plasma. This metabolite has minimal antifungal activity and does not affect the overall efficacy of voriconazole.

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

After administration of radiolabeled voriconazole, approximately 80% of radioactivity was recovered in urine after multiple intravenous doses and 83% after multiple oral doses. The majority (>94%) of radiolabeled 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, the half-life is not used to assess accumulation or elimination of voriconazole. Pharmacokinetics in special patient populations

Gender. In a study of multiple oral dosing of voriconazole, 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 of study participants. Safety profiles and plasma concentrations of voriconazole in women and men were similar. Therefore, no dose adjustment of voriconazole based on patient gender is necessary.

Elderly patients. In a clinical study of multiple oral dosing of voriconazole, Cmax and AUCτ levels in healthy elderly men 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). In clinical studies, dose adjustment was not performed based on patient age. An association between plasma drug concentration and patient 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").

Children. The recommended oral dose of voriconazole for children is based on pharmacokinetic analyses of data obtained from 112 immunocompromised children aged 2–12 years and 26 immunocompromised children aged 12–17 years. Multiple doses of 3 mg/kg, 4 mg/kg, 6 mg/kg, 7 mg/kg, 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 3 pharmacokinetic studies involving 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 involving children. In this patient category, greater individual variability was observed compared to adults. Comparison of pharmacokinetic parameters in children and adults showed that the expected total exposure (AUCτ) in children after a loading dose of 9 mg/kg intravenously was comparable to AUCτ in adults after a loading dose of 6 mg/kg intravenously. AUCτ in children after maintenance doses of 4 mg/kg and 8 mg/kg twice daily intravenously was comparable to AUCτ in adults after 3 mg/kg and 4 mg/kg twice daily intravenously. AUCτ in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults after 200 mg orally twice daily. Exposure to voriconazole after an intravenous dose of 8 mg/kg will be twice higher than after an oral dose of 9 mg/kg. The higher maintenance dose for intravenous administration in children compared to adults reflects greater elimination capacity due to higher liver mass relative to body weight. Oral bioavailability of voriconazole may be reduced in children with malabsorption and very low body weight for age. In such cases, intravenous voriconazole is recommended. Voriconazole exposure 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. It appears that in such patients, voriconazole metabolism resembles that in children rather than adults. Based on population pharmacokinetic analysis, children aged 12–14 years with body weight below 50 kg should receive pediatric doses (see section "Dosage and administration").

Renal impairment. In patients with moderate to severe renal impairment (serum creatinine < 2.5 mg/dL), accumulation of sulfobutylether-β-cyclodextrin sodium occurs (see sections "Special precautions" and "Dosage and administration").

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

In a clinical study of multiple oral administration of voriconazole, 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 voriconazole twice daily. Pharmacokinetic data for voriconazole 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.

The medicinal product should be used in adults and children for the treatment of:

• invasive aspergillosis;
• candidemia not associated with 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, quinidine, or ivabradine, as increased plasma concentrations of these medicinal products may lead to QTc interval prolongation and, rarely, to development of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use with rifampicin, carbamazepine, phenobarbital, and St. John's wort, as these medicinal products can significantly reduce voriconazole plasma concentrations (see section "Interaction with other medicinal products and other types of interactions").
• 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 types of interactions"; for use at lower 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 (see section "Interaction with other medicinal products and other types of interactions"; 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 agents may result in ergotism (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use of voriconazole with naloxegol, a CYP3A4 substrate, as increased naloxegol plasma concentrations may trigger opioid withdrawal symptoms (see section "Special precautions for use").
• 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 increases in lurasidone exposure may lead to serious adverse reactions (see section "Interaction with other medicinal products and other types of interactions").
• 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 types of interactions").

Interaction with other medicinal products and other types of interactions.

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. This is particularly relevant for substances metabolized by CYP3A4, as voriconazole is a strong inhibitor of CYP3A4, although the magnitude 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 groups and different routes of administration.

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

Information on interactions between voriconazole and other medicinal products is provided in Table 6. 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 Table 6 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;
н/з – not applicable.

Interactions in Table 6 are listed in the following order: concomitant use is contraindicated, concomitant use requires dose adjustment and careful clinical and biological monitoring, concomitant use does not demonstrate significant pharmacokinetic interactions but may raise clinical concern within this therapeutic area.

Table 6

Special precautions for use.

Hypersensitivity. The medicinal product should be used with caution in patients with hypersensitivity to other azoles (see section "Side effects").

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 observed in patients with risk factors such as history of 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 arrhythmias;
• concomitant use of medicinal products that may prolong the QTc interval.

Electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and, if necessary, corrected before initiating voriconazole treatment and during therapy (see section "Dosage and administration"). A study in healthy volunteers assessed the effect of single doses of voriconazole up to 4 times higher than the standard daily dose on the QTc interval. In none of the study participants did the duration of this interval exceed the potentially clinically significant threshold of 500 ms (see section "Pharmacodynamics").

Reactions related to intravenous infusion.

Reactions associated with infusion of voriconazole have been observed during administration, primarily flushing and nausea. Depending on the severity of symptoms, consideration should be given to discontinuing therapy (see section "Side effects").

Hepatotoxicity.

Serious hepatic reactions (including clinically apparent hepatitis, cholestasis, and fulminant hepatic failure, including fatal cases) have been observed during clinical trials with voriconazole. 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 liver function tests usually normalized after discontinuation of therapy (see section "Side effects").

Liver function monitoring. Patients receiving Vorikotsid 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 risk/benefit assessment (see section "Dosage and administration"), the frequency of monitoring may be reduced to once monthly provided there are no changes in liver function tests.

If liver function tests show significant elevation, Vorikotsid should be discontinued, except in cases where medical evaluation of the risk/benefit ratio justifies continued use of voriconazole. Liver function monitoring is required in both children and adults. Serious skin-related adverse reactions.

• Phototoxicity. Voriconazole use has additionally been associated with phototoxic reactions such as freckles, lentigo, actinic keratosis, and pseudoporphyria. All patients, including children, should avoid direct sunlight exposure, wear protective clothing, and use a high-protection sunscreen (SPF) during voriconazole therapy.
• Squamous cell carcinoma of the skin. Among patients who developed squamous cell carcinoma of the skin, some had previously experienced phototoxic reactions. In case of phototoxic reactions, multidisciplinary physician consultations should be conducted, voriconazole therapy discontinued, alternative antifungal agents considered, and the patient referred to a dermatologist. If voriconazole treatment continues, a dermatologist should systematically and regularly examine the patient for early detection and treatment of potential premalignant lesions. Voriconazole therapy should be discontinued if premalignant skin lesions or squamous cell carcinoma are detected (see section "Long-term therapy" below).
• Severe skin-related adverse reactions. Serious skin-related adverse 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 during voriconazole therapy. Patients presenting with rashes should be closely monitored, and voriconazole should be discontinued if signs of disease progression occur.

Adrenal gland effects.

Adrenal insufficiency has occurred in some patients during treatment with other azoles (e.g., ketoconazole).

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

Patients undergoing long-term voriconazole therapy with corticosteroids (including inhaled, e.g., budesonide, and intranasal corticosteroids) should be closely monitored for adrenal cortex dysfunction both during and after voriconazole treatment (see section "Interaction with other medicinal products and other forms of interaction"). Long-term therapy. Long-term use of voriconazole (for treatment or prophylaxis) beyond 180 days (6 months) requires careful assessment of benefit/risk ratio. Additionally, physicians should consider reducing the voriconazole dose (see sections "Pharmacodynamics" and "Dosage and administration").

Cases of squamous cell carcinoma of the skin associated with long-term voriconazole use have been reported.

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

Ocular side effects. Prolonged ocular side effects, including blurred vision, optic neuritis, and optic disc edema, have been reported (see section "Side effects").

Renal side effects. Acute renal failure has been reported during voriconazole use in patients with severe illnesses. Renal function may decrease in patients receiving voriconazole concomitantly with nephrotoxic medicinal products and/or underlying conditions (see section "Side effects").

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 voriconazole use. Monitoring of serum amylase or lipase levels may be necessary.

Children. Safety and efficacy of voriconazole use in children under 2 years of age have not been established (see sections "Pharmacodynamics" and "Side effects"). Voriconazole is recommended for use in children aged 2 years and older. Elevated liver enzymes have been observed more frequently in children (see section "Side effects"). Liver function monitoring is required in both adults and children. In patients aged 2–12 years, oral bioavailability of the medicinal product may be limited due to malabsorption and very low body weight. Intravenous administration is recommended for such patients.

Serious skin-related adverse reactions (including squamous cell carcinoma of the skin). The incidence of phototoxic reactions is higher in children. If lesions progress toward squamous cell carcinoma in patients in this group, enhanced protective measures against sunlight exposure should be taken. Children exhibiting signs of photoaging, such as freckles or lentigo, should be monitored by a dermatologist and avoid sunlight exposure even after discontinuation of voriconazole.

Prevention. In case of treatment-related adverse reactions (hepatotoxicity, severe skin reactions including phototoxicity and squamous cell carcinoma, severe or prolonged visual disturbances, and periostitis), consideration should be given to discontinuing voriconazole and using alternative antifungal agents.

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

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

Rifabutin (potent CYP450 inducer). Careful monitoring of complete blood count parameters and rifabutin-related adverse reactions (such as uveitis) is necessary during concomitant use of voriconazole and rifabutin. 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 risk (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

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

Methadone (CYP3A4 substrate). Careful monitoring for development of adverse reactions and signs of methadone toxicity (including QTc interval prolongation) is recommended during concomitant use of methadone and voriconazole, 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 are used concomitantly with voriconazole, consideration should be given to reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil) (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of opioid-related adverse reactions (including prolonged monitoring of respiratory function) may be necessary, as the half-life of alfentanil is prolonged fourfold with concomitant voriconazole use, and according to independently published study data, concomitant use of fentanyl and voriconazole led to increased mean AUC0-∞ of fentanyl.

Long-acting opioids (CYP3A4 substrates). When long-acting opioids are used concomitantly with voriconazole, consideration should be given to reducing the dose of oxycodone and other CYP3A4-metabolized long-acting opioids (e.g., hydrocodone). 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 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").

Disposal of unused medicinal product or medicinal product with expired shelf life.

Environmental release of the medicinal product should be minimized. The medicinal product should not be disposed of via wastewater or household waste. "Waste collection systems" should be used for disposal if available. Any unused medicinal products or waste must be disposed of in accordance with local requirements.

Important information about excipients.

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

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 for humans is unknown. Voriconazole should not be used during pregnancy except when the expected benefit to the pregnant woman 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 period. Excretion of voriconazole into breast milk has not been studied; therefore, breastfeeding should be discontinued during voriconazole therapy.

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. Voriconazole use 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 the medicinal product Vorikotsid and during its administration, monitoring for electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia is required, and correction should be performed if necessary (see section "Special Warnings and Precautions for Use").

The medicinal product Vorikotsid is recommended to be administered at a maximum rate of 3 mg/kg/hour over 1–3 hours.

Treatment

Adults.

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

Table 7

* Including patients aged 15 years and older.

Duration of treatment. The duration of treatment should be as short as possible, depending on the clinical and mycological response of the patient. If prolonged use of voriconazole beyond 180 days (6 months) is necessary, a careful benefit-risk assessment should be performed (see sections "Pharmacodynamics" and "Special warnings and precautions for use"). Dose adjustment in adults. If patients are unable to tolerate intravenous voriconazole 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 in the patient, the maintenance dose may be increased to 300 mg twice daily orally. Patients with body weight less than 40 kg may have the voriconazole dose increased to 150 mg twice daily orally.

For patients who cannot tolerate higher doses of voriconazole, the dose should be gradually reduced by 50 mg until reaching a maintenance dose of 200 mg twice daily orally (or 100 mg twice daily orally for patients with body weight less than 40 kg).

If treatment-related adverse reactions occur, consideration should be given to discontinuing voriconazole and initiating alternative antifungal agents (see sections "Pharmacodynamics" and "Adverse reactions"). Dose adjustment when used concomitantly with other medicinal products. Rifabutin or phenytoin may be used concomitantly with voriconazole provided the maintenance dose of voriconazole is increased to 5 mg/kg twice daily intravenously (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Efavirenz may be used concomitantly with voriconazole provided the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the dose of efavirenz is reduced by 50%, i.e., to 300 mg once daily. After discontinuation of voriconazole, the initial dose of efavirenz should be resumed (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Geriatric 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 sodium sulfobutyl ether β-cyclodextrin occurs. These patients should receive voriconazole orally, except in cases where the benefit of intravenous voriconazole outweighs the risks. These patients require close 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 of voriconazole.

The clearance of sodium sulfobutyl ether β-cyclodextrin during hemodialysis is 55 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 tests (AST, ALT, alkaline phosphatase, and total bilirubin more than 5 times the upper limit of normal) is limited. Voriconazole use has been associated with elevated liver function parameters and clinical signs of liver injury, such as jaundice; therefore, voriconazole should be used in patients with severe hepatic impairment only if the expected benefit outweighs the potential risk. Close monitoring for drug-induced toxic effects is required in patients with severe hepatic impairment (see section "Adverse reactions").

Method of administration.

Before administration as an intravenous infusion, the medicinal product must be reconstituted and diluted. Voriconazole 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 injections or in 19 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion. Do not use the vial of Vorikotsid if the solvent does not get drawn into the vial by vacuum force. It is recommended to use a standard (non-automatic) 20 ml syringe to ensure accurate addition of 19 ml of water for injections or 9 mg/ml (0.9%) sodium chloride solution for infusion.

The medicinal product is intended for single use only; only clear solutions free from particulate matter 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 concentration of 0.5–5 mg/ml.

Table 8

Required volumes of Vorikotsid concentrate (10 mg/ml)

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 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 portion of the solution should be discarded according to local requirements.

Information on the use of the medicinal product for prophylaxis is provided below. Prophylaxis in adults and children.

Prophylaxis should be initiated on the day of transplantation; its duration may extend up to 100 days. Prophylaxis should be as short as possible depending on the risk of developing invasive fungal infections, determined by signs of neutropenia or immunosuppression. Extending prophylaxis up to 180 days after transplantation may be considered only in cases of ongoing immunosuppression or graft-versus-host disease. Dosing. The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups (see Tables 4 and 5).

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

The information provided below applies to both treatment and prophylaxis.

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

Children.

Voriconazole 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 voriconazole 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

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

Dose adjustment for pediatric patients aged 2–12 years and those aged 12–14 years with body weight < 50 kg: If the patient's response to treatment is inadequate, the intravenous dose of voriconazole may be increased by 1 mg/kg increments. If the patient does not tolerate the treatment, the intravenous dose of voriconazole should be reduced by 1 mg/kg decrements.

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

Overdose.

Symptoms. There have been three reported cases of accidental overdose. All 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 sulfobutyl ether β-cyclodextrin during hemodialysis is 55 mL/min.
Treatment. In cases of overdose, hemodialysis may aid in the elimination of voriconazole and sodium sulfobutyl ether β-cyclodextrin from the body.

Adverse Reactions

The safety profile of voriconazole in adults is based on data from an integrated safety database encompassing more than 2000 individuals (including 1603 adult patients who participated in therapeutic studies) and an additional 270 adult patients from prophylaxis studies. 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 generally mild to moderate in severity. Analysis of safety data showed no clinically significant differences according to patient age, race, or gender.

Since most studies were open-label, all adverse reactions listed below are those that may be causally related to voriconazole use. Adverse reactions are defined based on pooled data from 1873 adult patients participating in therapeutic (1603) and prophylaxis (270) studies. Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from 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*

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, peripheral edema

Metabolism and nutrition disorders

Very common: Hypoglycemia, hypokalemia, hyponatremia

Psychiatric disorders

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

Nervous system disorders

Very common: Headache
Common: Seizures, syncope, tremor, hypertension³, paresthesia, somnolence, dizziness
Uncommon: Brain edema, encephalopathy⁴, extrapyramidal disorders⁵, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia
Rare: Hepatic encephalopathy, Guillain-Barré syndrome, nystagmus

Eye disorders

Very common: Visual disturbance⁶
Common: Retinal hemorrhage
Uncommon: Optic nerve disorders⁷, optic disc edema⁸, ocular hypertensive crisis, diplopia, scleritis, blepharitis
Rare: Optic nerve atrophy, corneal opacity

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: 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, angioneurotic edema, 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: Pyrexia
Common: Chest pain, facial edema¹¹, asthenia, chills
Uncommon: Infusion site reaction, influenza-like illness

Investigations

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

* Adverse reactions identified after voriconazole marketing authorization.

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 Prolonged optic neuritis 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 exertional dyspnea.
¹⁰ Includes drug-induced liver injury, toxic hepatitis, hepatocellular injury, and hepatotoxicity.
¹¹ Includes periorbital edema, lip edema, and oral tissue edema.

Visual disturbances
During clinical and therapeutic studies, visual disturbances (particularly blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorders, presence of rainbow halos in visual field, night blindness, oscillopsia, photopsia, flickering scotoma, reduced visual acuity, visual brightness, visual field defect, floaters, and xanthopsia) were very commonly observed and associated with voriconazole use. These visual disturbances were transient and fully reversible, resolving spontaneously in most cases within 60 minutes; no clinically significant long-term visual effects were observed. Symptoms tended to diminish with repeated dosing. Visual disturbances were generally mild, rarely led to discontinuation of voriconazole, and were not associated with long-term consequences. Visual disturbances may be related to high plasma concentration and/or dose of voriconazole.

The mechanism of visual disturbances is unknown, although the drug is likely to affect the retina. Voriconazole administration resulted in 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 completely 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 studies; however, these patients were also receiving multiple other medications for treatment of serious 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), occurred during voriconazole use (see section "Special Warnings and Precautions for Use").

Patients developing rashes should be closely monitored, and voriconazole should be discontinued if skin lesions progress. Cases of serious photosensitivity reactions, including freckles, lentigo, and actinic keratosis, have been reported, particularly during prolonged voriconazole use (see section "Special Warnings and Precautions for Use").

Cases of cutaneous squamous cell carcinoma have been reported in patients receiving long-term voriconazole; the mechanism of this phenomenon is not yet 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 treatment or prophylaxis. Abnormal liver function test results may be associated with high plasma concentration and/or dose of voriconazole. Most abnormalities resolved during continued voriconazole therapy without dose adjustment or after dose modification, 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 allogeneic hematopoietic stem cell transplant recipients without prior 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 liver adverse reactions led to complete discontinuation of the study 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 treatment (105) in clinical studies. 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, there was a trend toward more frequent elevation of liver enzymes in children compared to adults (transaminase elevation frequency was 14.2% in children vs. 5.3% in adults), reported as an adverse reaction in clinical studies. Post-marketing experience suggests that the incidence of skin adverse 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, which could not be excluded as being related to voriconazole, were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), increased blood bilirubin (1), increased liver enzymes (1), rash (1), and optic disc edema (1). Pancreatitis has also been reported in children receiving voriconazole during the post-marketing period.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine 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.
Store in the original packaging at temperatures not exceeding 25 °C. Keep out of reach of children.

The 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 solution should be used immediately. If not used immediately, the storage period should generally not exceed 24 hours at 2–8 °C (refrigerated), 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 medicinal products using the same infusion line or cannula. After completion of the infusion, the infusion line may be used for administration of other intravenous drugs.

Blood products and short-term infusions of concentrated electrolyte solutions: Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to initiating voriconazole therapy. Voriconazole must not be administered simultaneously with any blood product or any short-term infusion of concentrated electrolyte solutions, even if infusions are administered through separate lines.

Total parenteral nutrition (TPN): TPN should not be discontinued during administration of the medicinal product but should be administered through a separate infusion line. When using a multi-lumen catheter, TPN should be administered through a separate port, not through the port used for voriconazole infusion. The 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. 200 mg powder in a vial. 1 vial per carton.

Prescription category. Prescription only.

Manufacturers.
FARMATEN S.A.
ANFARM HELLAS S.A.

Manufacturer addresses and locations of operations.
Dervenakion 6, Pallini Attica, 15351, Greece.
61st km National Road Athens-Lamia, Schimatari Viotia 32009, Greece.