Kandivor

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

Composition:

Active substance: voriconazole;

1 vial contains 200 mg of voriconazole;

Excipient: sodium sulfobutyl ether beta-cyclodextrin.

Pharmaceutical form. Lyophilisate for solution for infusion.

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

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives.

ATC code J02A C03.

Pharmacological Properties

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

Pharmacokinetics/Pharmacodynamics. Across 10 therapeutic studies, the median plasma concentrations for each individual patient were 2425 ng/mL (interquartile range 1193–4380 ng/mL) for mean concentrations and 3742 ng/mL (interquartile range 2027–6302 ng/mL) for maximum concentrations, respectively. A positive correlation between mean, maximum, or minimum plasma concentrations of voriconazole and efficacy was not established in therapeutic or prophylactic studies.

Studies have shown a positive relationship between voriconazole plasma concentrations and abnormalities in liver function tests as well as visual disturbances. Dose adjustment has not been established in prophylactic studies.

Clinical efficacy and safety. In vitro, voriconazole demonstrates a broad spectrum of antifungal activity against Candida species (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all tested Aspergillus species. Additionally, voriconazole exhibits in vitro fungicidal activity against emerging fungal pathogens such as Scedosporium and Fusarium, 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, 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 against which voriconazole has shown efficacy (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 investigations (serological, histopathological) should be obtained to isolate and identify the causative pathogenic microorganisms. Therapy may be initiated before culture and laboratory results are available; however, once results become available, etiologic therapy should be adjusted accordingly.

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

However, in vitro activity of voriconazole against various Candida species is not uniform. In particular, for C. glabrata, the MIC of voriconazole is proportionally higher in 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 clinical breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1

EUCAST Breakpoints

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

Infections due to Aspergillus: efficacy in patients with poor-prognosis aspergillosis. Voriconazole demonstrates in vitro fungicidal activity against various species of Aspergillus. The efficacy and survival benefits of voriconazole 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 the results of a previous prospective study, which showed a positive treatment outcome in patients with poor-prognosis risk factors, including graft-versus-host reaction 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, as well as in patients with hematologic malignancies, solid 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 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. According to the primary analysis, favorable response to treatment, as assessed by the blinded data review committee, was defined as disappearance/reduction 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 evaluated 12 weeks after completion of therapy were considered unfavorable. Based on this analysis, favorable treatment outcomes were observed in 41% of patients in both treatment groups.

In a secondary analysis using assessments by the data review committee at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after completion of therapy), the rates of favorable response to voriconazole and to amphotericin B followed by fluconazole were 65% and 71%, respectively. The rates of favorable treatment 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 failed. 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, 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). Clinical efficacy data were supported by limited data on pathogen susceptibility to the drug.

Infections caused by various species of Scedosporium and Fusarium. The efficacy of voriconazole against the following 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, 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 the 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 (HSCT) recipients without prior confirmed or suspected invasive fungal infection (IFI). Voriconazole was compared with itraconazole as a primary prophylactic agent in an open-label, multicenter, comparative study in adults and adolescents undergoing allogeneic HSCT, without prior confirmed or suspected IFI. Success was defined as the ability to continue prophylaxis with the study drug for 100 days post-HSCT (continuously for >14 days) and survival without confirmed or suspected IFI within 180 days post-HSCT. The modified "intention-to-treat" (ITT) population included 465 allogeneic HSCT recipients, of whom 45% had acute myeloid leukemia (AML). Of all patients, 58% underwent myeloablative conditioning regimens. Prophylaxis with the study drug was initiated immediately after HSCT: 224 patients received voriconazole and 241 received itraconazole. The mean duration of study drug 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 endpoint of the study.

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

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

Table 4

Acute Myeloid Leukemia

• Primary endpoint of the study.

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

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

Table 5

Myeloablative conditioning regimen

* 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 IFI: efficacy in HSCT recipients with previously confirmed or suspected IFI. Voriconazole was studied as a secondary prophylactic agent in an open-label, non-comparative, multicenter study in adult recipients of allogeneic HSCT with previously confirmed or suspected IFI. The primary endpoint was the incidence of confirmed or suspected IFI within the first year after HSCT. The ITT population included 40 patients with prior IFI, 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.

Confirmed or suspected IFI occurred in 7.5 % (3/40) of patients within the first year after HSCT, including one case of candidemia, one case of Scedosporiosis (both were recurrences of prior IFI), and one case of zygomycosis. The survival rate at 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 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 modified intent-to-treat (mITT) efficacy analyses. The second study included 22 patients with invasive candidiasis, including candidemia and esophageal candidiasis, requiring primary or salvage therapy. Of these patients, 17 were included in the mITT efficacy analyses. In patients with invasive aspergillosis, the overall response rate at 6 weeks was 64.3 % (9 out of 14); the 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, it 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 voriconazole and ketoconazole were administered orally. 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 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 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 studied—namely, rate and uniformity 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 (area under the concentration-time curve [AUCτ]). An oral loading dose of 200 mg (or 100 mg for patients with body weight below 40 kg) achieves exposure equivalent to 3 mg/kg intravenous administration. An oral loading dose of 300 mg (or 150 mg for patients with body weight below 40 kg) achieves exposure equivalent to 4 mg/kg intravenous administration. When loading doses of voriconazole are administered orally or intravenously, plasma concentrations close to steady-state are achieved within the first 24 hours of therapy. Without a loading dose regimen, multiple dosing of voriconazole twice daily results in accumulation and attainment of steady-state plasma concentrations 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 %. With multiple dosing of voriconazole taken with a high-fat meal, Cmax and AUCτ decreased by 34 % and 24 %, respectively. Changes in gastric pH do not affect voriconazole absorption.

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

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

In vivo studies 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 healthy volunteers of Caucasian and Mongoloid (Japanese) races demonstrated that in "slow metabolizers" of voriconazole, the AUCτ of the drug is on average 4 times higher than in the comparison group—homozygous "rapid metabolizers" of voriconazole. Heterozygous "rapid metabolizers" of voriconazole have on average a 2-fold higher drug exposure than the comparison group—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; 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 after multiple intravenous doses and 83 % after multiple oral doses. The majority (> 94 %) of radioactive substances were eliminated within the first 96 hours after both intravenous and oral administration.

The half-life of voriconazole depends on the dose and is approximately 6 hours after oral administration of a 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 were observed between these parameters in 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 clinical study of multiple oral dosing, 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).

In clinical studies, dose adjustment was not performed based on age. 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").

Children. The recommended oral dose for children is based on pharmacokinetic analysis of data from 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 (powder for oral suspension) were evaluated in three pharmacokinetic studies involving children. Loading doses of 6 mg/kg twice daily intravenously on day 1, followed by 4 mg/kg twice daily intravenously and 300 mg twice daily orally (tablets), were evaluated in one pharmacokinetic study involving children. This patient category showed greater individual variability compared to adults.

Comparison of pharmacokinetic parameters in 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 intravenous maintenance doses of 4 and 8 mg/kg twice daily was comparable to AUCτ in adults after intravenous doses of 3 and 4 mg/kg twice daily. AUCτ in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults after an oral dose of 200 mg 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 may be reduced in children with malabsorption and 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, lower exposure to voriconazole was observed in some older children with low body weight compared to adults. It appears that in these patients, voriconazole metabolism is similar to that in children rather than in 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 level < 2.5 mg/dL), accumulation of sulfobutylether beta-cyclodextrin sodium occurs (see sections "Dosage and administration" and "Special precautions").

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

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

Clinical characteristics

Indications

Candivour is a broad-spectrum antifungal agent of the triazole class, indicated for adults and children aged 2 years and older for the treatment of:

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

The medicinal product should primarily be used in patients with progressive or potentially life-threatening infections.

Prophylactic use for invasive fungal infections in recipients at high risk undergoing allogeneic hematopoietic stem cell transplantation.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, or ivabradine — as increased plasma concentrations of these medicinal products may lead to QTc interval prolongation and rarely to the development of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other 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 lower doses, see section "Special precautions").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily) — as such ritonavir doses lead to a significant reduction in voriconazole plasma concentrations in healthy volunteers (see section "Interaction with other medicinal products and other types of interactions"; for lower doses, see section "Special precautions").
• 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 concentration may trigger opioid withdrawal symptoms (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use of voriconazole with tolvaptan — as strong CYP3A4 inhibitors such as voriconazole significantly increase tolvaptan plasma concentration (see section "Special precautions").
• Concomitant use of voriconazole with lurasidone — as substantial increase in lurasidone exposure may lead to serious adverse reactions (see section "Interaction with other medicinal products and other 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 concentration 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 extent of AUC increase depends on the substrate (see table below).

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 applied to other patient groups and other routes of administration.

Voriconazole should be used with caution in patients receiving concomitant 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 (some antihistamines, quinidine, cisapride, pimozide, and ivabradine), their concomitant use is contraindicated (see below and section "Contraindications").

Interactions of voriconazole with other medicinal products are shown in Table 6. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio and means: "within the 80–125% range" (↔), "below the 80–125% range" (↓), "above the 80–125% range" (↑). An asterisk (*) indicates bidirectional interaction. AUCτ — area under the curve over the dosing interval, AUCt — area under the curve from zero to a specified time point, AUC0–∞ — area under the curve from zero to infinity, n/a — not applicable.

Interactions in Table 6 are listed in the following order: concomitant use contraindicated, concomitant use requires dose adjustment and careful clinical and biological monitoring, concomitant use does not cause significant pharmacokinetic interactions but may be of clinical interest.

Table 6

Special precautions for use

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

Duration of use. Intravenous voriconazole should not be used 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 use of drugs that may induce this condition. Voriconazole should be used with caution in patients with potentially proarrhythmic conditions, such as:

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

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

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

Hepatotoxicity. During clinical trials, serious hepatic reactions (including clinically evident hepatitis, cholestasis, and fulminant hepatic failure, including fatal cases) 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, were observed in patients without other identified risk factors. Liver function abnormalities were reversible and usually resolved after discontinuation of therapy (see section "Adverse reactions").

Liver function monitoring. Patients receiving voriconazole should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (particularly aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels) 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 continued based on risk/benefit assessment (see section "Dosage and administration"), the frequency of monitoring may be reduced to once monthly in the absence of changes in liver test results.

If liver test results show significant elevation, the drug should be discontinued, unless continued use is considered appropriate based on medical risk/benefit assessment.

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

Serious skin reactions

• Photosensitivity. The use of the drug has additionally been associated with photosensitivity reactions such as freckling, lentigo, actinic keratosis, and pseudoporphyria. There is a potential increased risk of skin reactions/toxicity with concomitant use of photosensitizing agents (e.g., methotrexate, etc.). All patients, including children, should avoid exposure to direct sunlight, wear protective clothing, and use sunscreen with high sun protection factor (SPF) during treatment.
• Squamous cell carcinoma of the skin. Among patients in whom squamous cell carcinoma of the skin (SCC) (including SCC in situ or Bowen's disease) was documented, there were patients who previously had photosensitivity reactions. In case of photosensitivity reactions, consultation with various specialists is required, and the patient should be referred to a dermatologist. Discontinuation of the drug and use of alternative antifungal agents should be considered. If treatment continues despite the development of photosensitivity-related lesions, patients should undergo systematic and regular dermatological examination for early detection and treatment of precancerous lesions. If precancerous skin lesions or squamous cell carcinoma are detected, the drug should be discontinued (see subsection "Long-term treatment" below).
• Severe skin reactions. Cases of severe skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported during treatment with the drug. Patients presenting with rash should be closely monitored, and the drug should be discontinued if signs of disease progression are present.

Adrenal gland effects

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients receiving corticosteroids, voriconazole-related inhibition of their metabolism via CYP3A4 may lead to corticosteroid excess and suppression of adrenal function (see section "Interaction with other medicinal products and other forms of interaction"). Cushing's syndrome, with or without subsequent adrenal insufficiency, has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

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

Long-term treatment. Long-term use of the drug (for treatment or prophylaxis) beyond 180 days (6 months) requires careful risk/benefit assessment; physicians should consider limiting drug exposure (see sections "Dosage and administration" and "Pharmacodynamics").

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

In patients who have undergone transplant surgery, non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed. If a patient develops bone pain and radiological signs suggest periostitis, multidisciplinary consultations should be conducted and discontinuation of the drug should be considered (see section "Adverse reactions").

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

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

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

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

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

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

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

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

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate). When voriconazole is used concomitantly with efavirenz, 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 "Dosage and administration", "Contraindications", and "Interaction with other medicinal products and other forms of interaction").

Glasdegib (CYP3A4 substrate)

Concomitant use of voriconazole is likely to increase plasma concentrations of glasdegib and increase the risk of QTc interval prolongation (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use cannot be avoided, careful ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrates)

Concomitant use of voriconazole with tyrosine kinase inhibitors metabolized by CYP3A4 is expected to increase plasma concentrations of tyrosine kinase inhibitors and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and careful clinical monitoring are recommended (see section "Interaction with other medicinal products and other forms of interaction").

Rifabutin (potent CYP450 inducer). Careful monitoring of complete blood count parameters and rifabutin-related adverse reactions (such as uveitis) is necessary when voriconazole is used concomitantly with rifabutin. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the 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 the benefit to the patient from voriconazole use outweighs the risk (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

Methadone (CYP3A4 substrate). Careful monitoring for adverse reactions and signs of methadone toxicity, including QTc interval prolongation, is recommended when methadone is used concomitantly with 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, consider 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"). Careful monitoring of opioid-related adverse reactions (including prolonged respiratory function monitoring) may be necessary, as the elimination 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 increases the mean AUC0–∞ of fentanyl.

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

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

Excipients

Sodium content. Each vial of the drug contains 217.6 mg of sodium, which should be considered when administering the drug to patients who need to control sodium intake.

Cyclodextrins. The lyophilisate for infusion solution contains cyclodextrins: 3200 mg of cyclodextrins in each vial, equivalent to 160 mg/mL when reconstituted in 20 mL of solvent (see section "Composition"). This may affect the properties (e.g., toxicity) of the active substance and other medicinal products. The safety aspects of cyclodextrins were studied during drug development and safety evaluation.

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

Use during pregnancy or breastfeeding

Pregnancy. There are insufficient data on the use of 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. Women of childbearing potential who may become pregnant should use effective contraception during treatment with the drug.

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

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 these 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 and during its administration, monitoring of 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 recommended infusion rate is up to 3 mg/kg/hour over 1–3 hours.

Candivor, lyophilisate for solution for infusion, 200 mg is intended for intravenous use only. Oral formulations of voriconazole are available from other manufacturers.

Treatment

Adults

To achieve plasma concentrations close to steady-state levels on the first day of treatment, therapy should be initiated with an appropriate loading dose regimen, either orally or intravenously. Due to the high bioavailability of the drug after oral administration (96%; see section "Pharmacokinetics"), 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.

** Oral formulations of voriconazole are available from other manufacturers.

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

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

If an adequate response to treatment is not achieved, 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).

For information on use of the medicinal product for prophylaxis, see below.

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

Since voriconazole metabolism in adolescents may be more similar to that in children than in adults, they should be dosed as children.

The recommended dosing regimen is as follows:

Table 8

* Oral formulations of voriconazole are available from other manufacturers.

Note: The dosing regimen is based on the findings of a population pharmacokinetic analysis of data from 112 immunocompromised children aged 2 to < 12 years and 26 immunocompromised adolescents aged 12–17 years.

Initiation of therapy with intravenous administration is recommended, and oral administration should only be considered after significant clinical improvement. An intravenous dose of 8 mg/kg provides approximately twice the exposure of voriconazole compared to an oral dose of 9 mg/kg.

Adolescents aged 12–14 years with body weight ≥ 50 kg and those aged 15–17 years regardless of body weight should receive the same voriconazole doses as adults.

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

Use of the drug in children aged 2–12 years with hepatic or renal impairment has not been studied (see sections "Adverse Reactions" and "Pharmacokinetics").

Prophylaxis in adults and children

Prophylaxis should be initiated on the day of transplantation and may be continued for up to 100 days. Prophylaxis should be as short as possible, depending on the risk of invasive fungal infection (IFI), determined by neutropenia or immunosuppression. Prophylaxis may be extended up to 180 days post-transplantation only in cases of ongoing immunosuppression or graft-versus-host disease (see section "Pharmacological Properties").

Dosing

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups (see tables above).

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 benefit-risk assessment (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

The following applies to both treatment and prophylaxis

Dose adjustment. Dose adjustment in the absence of efficacy or in case of adverse reactions is not recommended when the drug is used for prophylaxis.

If treatment-related adverse reactions occur, consideration should be given to discontinuing voriconazole and initiating alternative antifungal agents (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Dose selection when co-administered with other agents

Rifabutin or phenytoin may be co-administered 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 co-administered 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").

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

Renal impairment

In patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min), accumulation of sodium sulfobutylether-beta-cyclodextrin occurs. These patients should receive voriconazole orally, except when the benefit of intravenous voriconazole outweighs the risks. In such cases, careful monitoring of serum creatinine levels is required. If serum creatinine increases, consideration should be given to switching the route of voriconazole administration to oral (see section "Pharmacokinetics").

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

The clearance of sodium sulfobutylether-beta-cyclodextrin during hemodialysis is 55 mL/min.

Hepatic impairment

Patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B) should receive standard loading doses, but the maintenance dose should be halved (see section "Pharmacokinetics").

The use of the drug has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh Class C).

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

The use of the drug has been associated with elevated liver function test values and clinical signs of liver injury, such as jaundice; therefore, the drug should be used in patients with severe hepatic dysfunction only when the benefit outweighs the potential risk. Close monitoring for toxic effects of the drug is required in patients with hepatic impairment (see section "Adverse Reactions").

Method of administration

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

To obtain 20 mL of a clear concentrate containing 10 mg/mL of voriconazole, the lyophilisate 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 solvent is not 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 medicinal product is intended for single use only; only clear solutions free from mechanical particulates should be used.

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

Table 9

Required volumes of medicinal product concentrate (10 mg/mL)

The reconstituted solution may be diluted with the following solutions:

• 0.9% (9 mg/mL) 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 portion of the solution should be disposed of according to local requirements.

Storage recommendations for the medicinal product

From a microbiological standpoint, the product should be used immediately after reconstitution. If not used immediately, the user is responsible for the duration and conditions of storage prior to use; normally, the product should not be stored for more than 24 hours at 2 to 8°C (in a refrigerator), except when reconstitution has been carried out under controlled and validated aseptic conditions.

Physical and chemical stability of the solution has been demonstrated for 24 hours at 2 to 8°C.

Children

The medicinal product can be used in children aged 2 years and older.

Safety and efficacy of voriconazole in children under 2 years of age have not been established. Current available data are presented in the sections "Adverse reactions" and "Pharmacological properties", but dosage recommendations cannot be provided.

Overdose

Three cases of accidental overdose have been reported. All occurred in children who received intravenous doses nearly five times higher than the recommended dose. The only adverse reaction reported was photophobia lasting 10 minutes.

There is no known antidote for voriconazole.

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

In cases of overdose, hemodialysis may facilitate elimination of voriconazole and sodium sulfobutyl ether beta-cyclodextrin 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 studies. This patient population is sufficiently diverse and includes patients with hematologic 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 were 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. Analysis of safety data showed no clinically significant differences according to age, race, or gender.

Summary of adverse reactions

Since most studies were open-label, all adverse reactions potentially causally related to the use of the medicinal product are listed below. Adverse reactions are based on pooled data from 1873 adult patients who participated in therapeutic (1603) and prophylactic (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 (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed in patients receiving voriconazole

* Adverse reactions identified after marketing authorization.

** Frequency category is based on data from an observational study.

1 Including febrile neutropenia and neutropenia.

2 Including immune thrombocytopenic purpura.

3 Including nuchal rigidity and tetany.

4 Including hypoxic-ischemic encephalopathy and metabolic encephalopathy.

5 Including akathisia and parkinsonism.

6 See "Description of selected adverse reactions. Ocular disorders" below.

7 Prolonged optic neuritis has been reported after marketing authorization (see section "Special precautions for use").

8 See section "Special precautions for use".

9 Including dyspnea and exertional dyspnea.

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

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

Description of selected adverse reactions

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

The mechanism of visual disturbances is unknown, although the drug is likely to affect the retina. Voriconazole administration resulted in a reduction in the amplitude of waves 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.

Prolonged adverse reactions related to the eyes have been reported after marketing authorization (see section "Special precautions for use").

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

Patients developing rashes should be closely monitored, and if lesions progress, the drug should be discontinued.

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

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

Liver function tests. During the clinical development program, the overall incidence of transaminase elevations greater than 3 times the upper limit of normal (not necessarily considered an adverse reaction) was 18.0% (319/1768) in adults and 25.8% (73/283) in children receiving voriconazole for treatment and prophylaxis.

Abnormal liver function test results may be associated with high plasma concentrations and/or doses of the drug. Most abnormalities resolved during continued treatment 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. These reactions included jaundice, hepatitis, and hepatic failure with fatal outcome (see section "Special precautions for use").

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

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

Pediatric population. The safety of voriconazole was evaluated in 288 children aged 2–12 years (169) and aged 12 to 18 years (119), who received voriconazole for prophylaxis (183) and treatment (105) in clinical trials. The safety of voriconazole was also assessed in 158 children aged 2 to 12 years within compassionate use programs. Overall, the safety profile of voriconazole in children was similar to that in adults.

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 within compassionate use programs, the following adverse reactions, which cannot be excluded as being causally related to voriconazole, were observed: 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 in the post-marketing period.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities

The infusion of this medicinal product must not be administered simultaneously with other intravenous medicinal products using the same infusion line or cannula. The container should be inspected to ensure that the infusion is complete. After completion of voriconazole infusion, the same 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 initiating 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): TPN should not be discontinued during administration of the drug but should be administered through a separate infusion line. When administered via a multi-lumen catheter, TPN should be infused through a separate port, not through the port used for voriconazole infusion. The drug 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 "Method of administration and dosage".

Packaging. 1 vial of lyophilisate in a box.

Prescription status. Prescription only.

Manufacturer. Aspiro Pharma Limited.

Manufacturer’s address and place of business

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.

Date of last review.