Voriconazole rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORICONAZOLE ROMPHARM

Composition:

Active substance: voriconazole;

1 vial contains 200 mg of voriconazole;

Excipient: sodium sulfobutylether beta-cyclodextrin.

Pharmaceutical form. Lyophilisate for concentrate for solution for infusion.

Main physicochemical properties: white to almost white 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-demethylation of lanosterol, mediated by fungal cytochrome P450, 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.

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 relationship between mean, maximum, or minimum plasma concentrations of voriconazole and efficacy has not been established in therapeutic trials, and such a relationship has not been demonstrated in prophylactic studies.

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

Clinical efficacy and safety

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

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

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

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

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

Clinical breakpoints

Prior to initiating therapy, fungal cultures and other appropriate laboratory investigations (serological, histopathological) should be obtained to isolate and identify the causative microorganisms responsible for the infection. Therapy may be initiated before culture and laboratory results are available; however, once such results become available, targeted antimicrobial therapy should be adjusted accordingly.

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

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

EUCAST-defined breakpoints

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

Clinical Experience

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

Infections caused by Aspergillus: efficacy in patients with poor-prognosis aspergillosis

Voriconazole demonstrates in vitro fungicidal activity against various species of Aspergillus. The efficacy of voriconazole and its survival benefits compared to the standard comparator drug 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 for the treatment of sinus aspergillosis, cerebral, pulmonary, and disseminated aspergillosis in patients following bone marrow and solid organ transplantation, as well as in patients with hematologic malignancies, solid tumors, and AIDS.

Candidemia in non-neutropenic patients

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

In a secondary analysis using assessments by the Independent Data Review Committee at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after 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 the table below.

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

Severe refractory infections caused by Candida species

A clinical study included 55 patients with severe refractory systemic infections caused by Candida species (including candidemia, disseminated candidiasis, and other forms of invasive candidiasis), in whom prior antifungal therapy, including fluconazole, had been ineffective. A favorable response to voriconazole treatment was observed in 24 patients (15 with complete response, 9 with partial response). In patients infected with fluconazole-resistant non-Candida albicans strains, favorable outcomes with voriconazole therapy were observed in 3 out of 3 patients infected with C. krusei (all with complete response) and in 6 out of 8 patients infected with C. glabrata (5 with complete response, 1 with partial response). Data on clinical efficacy were supported by limited data on pathogen susceptibility to the drug.

Infections caused by various Scedosporium and Fusarium species

The efficacy of voriconazole against the following rare pathogenic fungi has been demonstrated:

• Scedosporium species: a favorable response to voriconazole therapy was observed in 16 out of 28 patients infected with S. apiospermum (6 patients with complete response, 10 with partial response) and in 2 out of 7 patients infected with S. prolificans (both with partial response). 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. Four additional patients with fusariosis were infected with multiple pathogens; favorable treatment outcomes were observed in 2 of these patients.

In the majority of patients who received voriconazole for the treatment of the above-mentioned rare fungal infections, intolerance or resistance to previously administered antifungal agents was observed.

Primary prophylaxis of invasive fungal infections: efficacy in hematopoietic stem cell transplant recipients without previously 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 previously confirmed or suspected invasive fungal infection. Success was defined as the ability to continue prophylaxis with the study drug for 100 days after hematopoietic stem cell transplantation (continuously for >14 days) and survival without confirmed or suspected invasive fungal infection during the 180 days following hematopoietic stem cell transplantation. The modified "intention-to-treat" (ITT) patient population included 465 recipients of allogeneic hematopoietic stem cell transplantation, of whom 45% had acute myeloid leukemia. Among all patients, 58% underwent myeloablative conditioning regimens. Prophylaxis with the study drug was initiated immediately after hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 patients received itraconazole. The mean 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 the table below.

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

* Primary study endpoint.

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

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

Acute myeloid leukemia

Primary endpoint	Voriconazole (N=98)	Itraconazole (N=109)	Difference in proportions and 95% confidence interval (CI)
Incidence of invasive fungal infection – day 180	1 (1.0%)	2 (1.8%)	–0.8% (–4.0%, 2.4%) **
Effectiveness at day 180*	55 (56.1%)	45 (41.3%)	14.7% (1.7%, 27.7%)***

• Primary endpoint of the study.

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

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

Myeloablative conditioning regimen

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

* Primary endpoint of the study.

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

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

Secondary prophylaxis of invasive fungal infection: efficacy in recipients of allogeneic hematopoietic stem cell transplantation with previously confirmed or suspected invasive fungal infection

Voriconazole was evaluated as a secondary prophylactic agent in an open-label, non-comparative, multicenter study in adult recipients of allogeneic hematopoietic stem cell transplantation with previously confirmed or suspected invasive fungal infection. The primary endpoint was the incidence of 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 prophylactic treatment with the study 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 trials, 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 efficacy analyses of the modified intent-to-treat (MITT) population. 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 MITT population. 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 it was 70% (7 out of 10). The combined overall response rate (in patients with candidemia and esophageal candidiasis combined) was 88.9% (8 out of 9) in patients aged 2 to 12 years and 62.5% (5 out of 8) in patients aged 12 to 18 years.

Clinical studies assessing QTc interval

A placebo-controlled, randomized, crossover study with single-dose administration in healthy volunteers was conducted to evaluate the effect of investigational agents on the QTc interval. Three doses of voriconazole and oral ketoconazole were administered. 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 subject had a QTc prolongation ≥ 60 ms from baseline. No subject exceeded the potentially clinically significant threshold of 500 ms.

Pharmacokinetics.

General pharmacokinetic characteristics

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

Voriconazole pharmacokinetics are non-linear due to extensive metabolism. As the dose increases, exposure increases more than proportionally. It is estimated that increasing the oral dose from 200 mg to 300 mg twice daily results in an average 2.5-fold increase in exposure (AUCτ). An oral loading dose of 200 mg (or 100 mg for patients with body weight below 40 kg) achieves exposure equivalent to an intravenous dose of 3 mg/kg. An oral loading dose of 300 mg (or 150 mg for patients with body weight below 40 kg) achieves exposure equivalent to an intravenous dose of 4 mg/kg. When loading doses of voriconazole are administered orally or intravenously, plasma concentrations approaching steady-state are achieved within the first 24 hours of therapy. Without a loading dose regimen, with repeated twice-daily administration, voriconazole accumulation and achievement 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 plasma concentration (Cmax) reached within 1–2 hours after dosing. Absolute bioavailability 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 does not affect voriconazole absorption.

Distribution

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

Metabolism

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

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. Among Caucasian and Negroid populations, the proportion of slow metabolizers is 3–5%. Studies conducted in healthy Caucasian and Japanese volunteers demonstrated that in "slow metabolizers" of voriconazole, drug exposure (AUCτ) is on average 4 times higher than in the comparator group of homozygous "rapid metabolizers." Heterozygous "rapid metabolizers" have on average 2 times higher drug exposure than homozygous "rapid metabolizers."

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

Excretion

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

After multiple intravenous or oral administration of radiolabeled voriconazole, approximately 80% and 83% of radioactivity, respectively, was recovered in urine. The majority (>94%) of radioactivity was excreted 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, 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, Cmax and AUCτ values in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18–45 years). No statistically significant differences in these parameters were observed between healthy elderly men and women (≥65 years). Dose adjustment based on gender was not performed in clinical trials. Safety profiles and plasma concentrations of the drug were similar in men and women. Therefore, dose adjustment based on gender is not necessary.

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

Dose adjustment based on age was not performed in clinical trials. 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 analyses from data obtained in 112 immunocompromised children aged 2–12 years and 26 immunocompromised children aged 12–17 years. Multiple doses of 3, 4, 6, 7, and 8 mg/kg twice daily intravenously and multiple oral doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily (oral suspension powder) were evaluated in three pharmacokinetic studies 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 pediatric pharmacokinetic study. This patient group showed greater inter-individual variability compared to adults.

Comparison of pharmacokinetic parameters between children and adults showed that the expected total exposure (AUCτ) in children after an intravenous loading dose of 9 mg/kg was comparable to AUCτ in adults after an intravenous loading dose of 6 mg/kg. AUCτ in children after 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 after an intravenous dose of 8 mg/kg is expected to be twice that 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 or very low body weight for age. In such cases, intravenous voriconazole is recommended.

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

Renal impairment. In patients with moderate to severe renal impairment (serum creatinine >2.5 mg/dL), accumulation of sulfobutyl ether β-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 was 233% higher than in patients with normal liver function. Hepatic impairment does not affect voriconazole plasma protein binding.

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

Clinical characteristics.

Indications.

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

Voriconazole Rompharm is indicated for treatment in adults and children:

• 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 and Fusarium species.

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

Contraindications.

Hypersensitivity to voriconazole or to any of the excipients listed in the section "Composition".

Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, or ivabradine — because increased plasma concentrations of these medicinal products may lead to QTc interval prolongation and rare cases of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use with rifampicin, carbamazepine, phenobarbital, or St. John’s wort — because these agents may significantly reduce plasma concentrations of voriconazole (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use of standard doses of voriconazole with efavirenz at a dose of 400 mg once daily or higher is contraindicated — because efavirenz significantly reduces plasma concentrations of voriconazole in healthy individuals at these doses. Voriconazole also significantly increases plasma concentrations of efavirenz (see section "Interaction with other medicinal products and other types of interactions"; for lower doses, see section "Special precautions for use").

Concomitant use with high-dose ritonavir (400 mg or more twice daily) — because ritonavir significantly reduces plasma concentrations of voriconazole in healthy individuals at this dose (see section "Interaction with other medicinal products and other types of interactions"; for lower doses, see section "Special precautions for use").

Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates — because increased plasma concentrations of these active substances may lead to ergotism (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use with sirolimus — because 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 — because increased plasma concentrations of naloxegol may precipitate opioid withdrawal symptoms (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use of voriconazole with tolvaptan — because strong CYP3A4 inhibitors such as voriconazole significantly increase tolvaptan plasma concentrations (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use of voriconazole with lurasidone — because 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 of voriconazole with venetoclax during initiation of venetoclax therapy and during the dose titration phase — because voriconazole may 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, respectively, voriconazole plasma concentrations. Voriconazole has the potential to increase plasma concentrations of substances metabolized by these cytochrome P450 isoenzymes; particularly relevant are substances metabolized by CYP3A4, as voriconazole is a strong inhibitor of CYP3A4, although the magnitude of AUC increase depends on the substrate (see table below).

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

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

The table below provides information on interactions between voriconazole and other medicinal products. The direction of arrows for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio.

Symbols and abbreviations used in the table and their meanings:

↔ — within 80–125%;
↑ — above 80–125%;
↓ — below 80–125%;
* — bidirectional interactions;
AUCτ — area under the concentration-time curve over the dosing interval;
AUCt — area under the concentration-time curve from time zero to a specified time point;
AUC0–∞ — area under the concentration-time curve from time zero to infinity;
n/a — not applicable.

Interactions in the table are presented in the following order:

• contraindicated;
• those requiring dose adjustment and careful clinical and/or biological monitoring;
• those without significant pharmacokinetic interaction but which may have clinical relevance.

Active substance [mechanism of interaction]	Interaction Mean geometric change, %	Recommendations for concomitant use
Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine [CYP3A4 substrates]	Although appropriate studies have not been conducted, increased plasma concentrations of these agents may lead to QTc prolongation and rarely to ventricular tachycardia of the torsade de pointes type	Contraindicated (see section "Contraindications")
Carbamazepine and long-acting barbiturates (e.g., phenobarbital, methohexital) [potent CYP450 inducers]	Despite the lack of appropriate studies, carbamazepine and long-acting barbiturates are likely to significantly reduce voriconazole plasma concentrations	Contraindicated (see section "Contraindications")
Efavirenz (non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; CYP3A4 inhibitor and substrate] 400 mg once daily concomitantly with voriconazole 200 mg twice daily* 300 mg once daily concomitantly with 400 mg voriconazole twice daily*	Cmax of efavirenz ↑ 38 % AUCτ of efavirenz ↑ 44 % Cmax of voriconazole ↓ 61 % AUCτ of voriconazole ↓ 77 % Compared to 600 mg efavirenz once daily: Cmax of efavirenz ↔ AUCτ of efavirenz ↑ 17 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 23 % AUCτ of voriconazole ↓ 7 %	Concomitant use of standard doses of voriconazole with efavirenz 400 mg once daily or higher is contraindicated (see section "Contraindications") When voriconazole and efavirenz are used concomitantly, the maintenance dose of voriconazole should be increased to 400 mg twice daily, and the efavirenz dose should be reduced to 300 mg once daily. After discontinuation of voriconazole, return to the initial efavirenz dose (see sections "Dosage and administration" and "Special precautions")
Ergot alkaloids (e.g., ergotamine and dihydroergotamine) [CYP3A4 substrates]	Although appropriate studies have not been conducted, voriconazole may increase plasma concentrations of ergot alkaloids and lead to ergotism	Contraindicated (see section "Contraindications")
Lurasidone [CYP3A4 substrate]	Although not studied, voriconazole is likely to significantly increase lurasidone plasma concentration.	Contraindicated (see section "Contraindications")
Naloxegol [CYP3A4 substrate]	Although not studied, voriconazole is likely to cause a significant increase in naloxegol plasma concentration	Contraindicated (see section "Contraindications")
Rifabutin [potent CYP450 inducer] 300 mg once daily 300 mg once daily (concomitantly with voriconazole 350 mg twice daily*) 300 mg once daily (concomitantly with voriconazole 400 mg twice daily*)	Cmax of voriconazole ↓ 69 % AUCτ of voriconazole ↓ 78 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↓ 4 % AUCτ of voriconazole ↓ 32 % Cmax of rifabutin ↑ 195 % AUCτ of rifabutin ↑ 331 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 104 % AUCτ of voriconazole ↑ 87 %	Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk. The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight below 40 kg) (see section "Dosage and administration"). When rifabutin and voriconazole are used concomitantly, careful monitoring of blood counts and rifabutin-related adverse reactions (e.g., uveitis) is recommended
Rifampicin (600 mg once daily) [potent CYP450 inducer]	Cmax of voriconazole ↓ 93 % AUCτ of voriconazole ↓ 96 %	Contraindicated (see section "Contraindications")
Ritonavir (protease inhibitor) [potent CYP450 inducer; CYP3A4 inhibitor and substrate] High doses (400 mg twice daily) Low doses (100 mg twice daily)*	Cmax and AUCτ of ritonavir ↔ Cmax of voriconazole ↓ 66 % AUCτ of voriconazole ↓ 82 % Cmax of ritonavir ↓ 25 % AUCτ of ritonavir ↓ 13 % Cmax of voriconazole ↓ 24 % AUCτ of voriconazole ↓ 39 %	Concomitant use of voriconazole and high-dose ritonavir (400 mg or higher twice daily) is contraindicated (see section "Contraindications"). Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless benefit outweighs risk
St. John's wort [CYP450 inducer; P-glycoprotein inducer] 300 mg three times daily (concomitant use with single 400 mg voriconazole dose)	In an independent published study, AUC0-∞ of voriconazole ↓ 59 %	Contraindicated (see section "Contraindications")
Tolvaptan [CYP3A4 substrate]	Although appropriate clinical studies have not been conducted, voriconazole is likely to significantly increase tolvaptan plasma concentrations	Contraindicated (see section "Contraindications")
Venetoclax [CYP3A substrate]	Although not studied, voriconazole is likely to significantly increase venetoclax plasma concentrations.	Concomitant use of voriconazole is contraindicated during initiation and dose-titration phases of venetoclax (see section "Contraindications"). Dose reduction of venetoclax is required as specified in the venetoclax product information during regular daily use; careful monitoring for signs of toxicity is recommended.
Fluconazole (200 mg once daily) [CYP2C9, CYP2C19 and CYP3A4 inhibitor]	Cmax of voriconazole ↑ 57 % AUCτ of voriconazole ↑ 79 % Cmax of fluconazole — not studied AUCτ of fluconazole — not studied	It is not established what dose reduction and/or frequency adjustment of voriconazole and fluconazole is necessary to avoid this effect. When voriconazole is used immediately after fluconazole, monitoring for voriconazole-related adverse reactions is recommended
Phenytoin [CYP2C9 substrate and potent CYP450 inducer] 300 mg once daily 300 mg once daily (concomitantly with 400 mg voriconazole twice daily)*	Cmax of voriconazole ↓ 49 % AUCτ of voriconazole ↓ 69 % Cmax of phenytoin ↑ 67 % AUCτ of phenytoin ↑ 81 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 34 % AUCτ of voriconazole ↑ 39 %	Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk. Close monitoring of phenytoin plasma levels is recommended Phenytoin may be used concomitantly with voriconazole provided the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily or from 200 mg to 400 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight below 40 kg) (see section "Dosage and administration")
Letermovir (CYP2C9 and CYP2C19 inducer)	Cmax of voriconazole ↓ 39 % AUC0-12 of voriconazole ↓ 44 % C12 of voriconazole ↓ 51 %	If concomitant use of voriconazole and letermovir cannot be avoided, monitoring for possible loss of voriconazole efficacy is required
Glasdegib [substrate CYP3A4]	Although not studied, likely to increase glasdegib plasma concentration and increase risk of QTc prolongation.	If concomitant use cannot be avoided, frequent ECG monitoring is recommended (see section "Special precautions")
Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) [substrates CYP3A4]	Although not studied, voriconazole may increase plasma concentrations of tyrosine kinase inhibitors metabolized by CYP3A4.	If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring are recommended (see section "Special precautions")
Anticoagulants Warfarin (single 30 mg warfarin dose concomitantly with 300 mg voriconazole twice daily) [CYP2C9 substrate] Other oral coumarins (e.g., phenprocoumon, acenocoumarol) [CYP2C9 and CYP3A4 substrates]	Maximum prothrombin time increased approximately twofold Although appropriate studies have not been conducted, voriconazole may increase plasma concentrations of coumarins and thereby prolong prothrombin time	Close monitoring of prothrombin time and other appropriate coagulation parameters is recommended, with dose adjustments of anticoagulants as needed
Ivacaftor [CYP3A4 substrate]	Although not studied, voriconazole is likely to increase ivacaftor plasma concentrations, increasing the risk of adverse effects	Dose reduction of ivacaftor is recommended
Benzodiazepines, [CYP3A4 substrates] Midazolam (single intravenous dose 0.05 mg/kg) Midazolam (single oral dose 7.5 mg) Other benzodiazepines (e.g., triazolam, alprazolam)	In an independent published study AUC0–∞ of midazolam ↑ ≈ 3.7-fold In an independent published study Cmax of midazolam ↑ 3.8-fold AUC0–∞ of midazolam ↑ ≈ 10.3-fold Although appropriate clinical studies have not been conducted, voriconazole is likely to increase plasma concentrations of benzodiazepines metabolized by CYP3A4 and prolong sedative effect	Dose reduction of benzodiazepines should be considered
Immunosuppressants [CYP3A4 substrates] Sirolimus (single 2 mg dose) Everolimus [also P-gp substrate] Cyclosporine (in stable renal transplant recipients on continuous cyclosporine therapy) Tacrolimus (single dose 0.1 mg/kg)	In an independent published study: Cmax of sirolimus ↑ 6.6-fold, AUC0-∞ of sirolimus ↑ 11-fold Although not studied, voriconazole is likely to significantly increase everolimus plasma concentration. Cmax of cyclosporine ↑ 13 % AUCτ of cyclosporine ↑ 70 % Cmax of tacrolimus ↑ 117 % AUCt of tacrolimus ↑ 221 %	Concomitant use of voriconazole and sirolimus is contraindicated (see section "Contraindications") Concomitant use of voriconazole and everolimus is not recommended due to expected significant increase in everolimus concentration (see section "Special precautions"). At initiation of voriconazole therapy in patients already receiving cyclosporine, a 50 % reduction in cyclosporine dose and close monitoring of its levels are recommended. Elevated cyclosporine levels are associated with nephrotoxic effects. After discontinuation of voriconazole, cyclosporine levels should be closely monitored and dose increased if necessary. At initiation of voriconazole therapy in patients already receiving tacrolimus, a reduction of tacrolimus dose to one-third of the initial dose and close monitoring of tacrolimus levels are recommended. Elevated tacrolimus levels are associated with nephrotoxic effects. After discontinuation of voriconazole, cyclosporine levels should be closely monitored and dose increased if necessary.
Long-acting opioids [CYP3A4 substrates] Oxycodone (10 mg single dose)	In an independent published study: Cmax of oxycodone ↑ 1.7-fold AUC0-∞ of oxycodone ↑ 3.6-fold	Dose reduction of oxycodone and other CYP3A4-metabolized long-acting opioids (e.g., hydrocodone) should be considered. Close and frequent monitoring for opioid-related adverse reactions is recommended.
Methadone (32–100 mg once daily) [CYP3A4 substrate]	Cmax of R-methadone (active) ↑ 31 % AUCτ of R-methadone (active) ↑ 47 % Cmax of S-methadone ↑ 65 % AUCτ of S-methadone ↑ 103 %	Continuous monitoring for adverse reactions and toxic effects associated with elevated methadone plasma concentrations, including QT prolongation, is recommended. Methadone dose reduction may be necessary.
Nonsteroidal anti-inflammatory drugs (NSAIDs) [CYP2C9 substrates] Ibuprofen (400 mg single dose) Diclofenac (50 mg single dose)	Cmax of S-ibuprofen ↑ 20 % AUC0-∞ of S-ibuprofen ↑ 100 % Cmax of diclofenac ↑ 114 % AUC0-∞ of diclofenac ↑ 78 %	Frequent monitoring for NSAID-related adverse reactions and toxicity is recommended. NSAID dose reduction may be necessary.
Omeprazole (40 mg once daily)* [CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]	Cmax of omeprazole ↑ 116 % AUCτ of omeprazole ↑ 280 % Cmax of voriconazole ↑ 15 % AUCτ of voriconazole ↑ 41 % Metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole, leading to increased plasma concentrations	No voriconazole dose adjustment is recommended. At initiation of voriconazole therapy in patients already receiving omeprazole (40 mg or higher), a 50 % reduction in omeprazole dose is recommended.
Oral contraceptives* [CYP3A4 substrates, CYP2C19 inhibitors] Norethisterone/ethinylestradiol (1 mg / 0.035 mg once daily)	Cmax of ethinylestradiol ↑ 36 % AUCτ of ethinylestradiol ↑ 61 % Cmax of norethisterone ↑ 15 % AUCτ of norethisterone ↑ 53 % Cmax of voriconazole ↑ 14 % AUCτ of voriconazole ↑ 46 %	Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended.
Short-acting opioids [CYP3A4 substrates] Alfentanil (20 μg/kg single dose, concomitantly with naloxone) Fentanyl (5 μg/kg single dose)	In an independent published study: AUC0-∞ of alfentanil ↑ 6-fold In an independent published study: AUC0-∞ of fentanyl ↑ 1.34-fold	Dose reduction of alfentanil, fentanyl, and other structurally similar CYP3A4-metabolized short-acting opioids (e.g., sufentanil) should be considered. Extended and frequent monitoring for respiratory depression and opioid-related adverse reactions is recommended.
Statins (e.g., lovastatin) [CYP3A4 substrates]	Although appropriate clinical studies have not been conducted, voriconazole is likely to increase plasma levels of statins metabolized by CYP3A4, potentially leading to rhabdomyolysis	If concomitant use of voriconazole with CYP3A4-metabolized statins cannot be avoided, consideration should be given to reducing the statin dose.
Sulfonylurea derivatives (e.g., tolbutamide, glipizide, glyburide) [CYP2C9 substrates]	Although appropriate studies have not been conducted, voriconazole may increase plasma levels of sulfonylurea derivatives and thereby cause hypoglycemia	Close monitoring of blood glucose levels is required. Consideration should be given to reducing the dose of sulfonylurea derivatives.
Vinca alkaloids (e.g., vincristine and vinblastine) [CYP3A4 substrates]	Although appropriate clinical studies have not been conducted, voriconazole is known to increase plasma levels of vinca alkaloids and may lead to neurotoxic effects	Dose reduction of vinca alkaloids should be considered.
Other HIV protease inhibitors (e.g., saquinavir, amprenavir, nelfinavir)* [substrates and inhibitors of CYP3A4]	Clinical studies have not been conducted. In vitro studies indicate that voriconazole may inhibit the metabolism of HIV protease inhibitors, and the metabolism of voriconazole may be inhibited by HIV protease inhibitors	Close monitoring of patients for signs of toxicity and/or lack of efficacy of these agents is recommended; dose adjustment may be required
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, nevirapine)* [substrates and inhibitors of CYP3A4 or CYP450 inducers]	Clinical studies have not been conducted. In vitro studies indicate that voriconazole metabolism may be inhibited by NNRTIs, and voriconazole may inhibit NNRTI metabolism. Based on studies of efavirenz's effect on voriconazole, voriconazole metabolism may be induced by NNRTIs	Close monitoring of patients for signs of toxicity and/or lack of efficacy of these agents is recommended; dose adjustment may be required
Tretinoin [CYP3A4 substrate]	Although not studied, voriconazole may increase tretinoin concentration and increase the risk of adverse reactions (pseudotumor cerebri, hypercalcemia)	Dose adjustment of tretinoin is recommended during and after voriconazole treatment
Cimetidine (400 mg twice daily) [non-specific CYP450 inhibitor, increases gastric pH]	Cmax of voriconazole ↑ 18 % AUCτ of voriconazole ↑ 23 %	No dose adjustment required
Digoxin (0.25 mg once daily) [P-glycoprotein substrate]	Cmax of digoxin ↔ AUCτ of digoxin ↔	No dose adjustment required
Indinavir (800 mg three times daily) [CYP3A4 inhibitor and substrate]	Cmax of voriconazole ↔ AUCτ of voriconazole ↔ Cmax of indinavir ↔ AUCτ of indinavir ↔	No dose adjustment required
Macrolide antibiotics Erythromycin (1 g twice daily) [CYP3A4 inhibitor] Azithromycin (500 mg once daily)	Cmax and AUCτ of voriconazole ↔ Cmax and AUCτ of voriconazole ↔ Effect of voriconazole on erythromycin or azithromycin is unknown	No dose adjustment required
Mycophenolic acid (1 g single dose) [UDP-glucuronosyltransferase substrate]	Cmax and AUCt of mycophenolic acid ↔	No dose adjustment required
Corticosteroids Prednisolone (60 mg single dose) [CYP3A4 substrate]	Cmax of prednisone ↑ 11 % AUC0-∞ of prednisone ↑ 34 %	No dose adjustment required. Patients undergoing long-term voriconazole and corticosteroid therapy (including inhaled, e.g., budesonide, and intranasal corticosteroids) should be closely monitored for adrenal insufficiency during and after voriconazole treatment (see section "Special precautions")
Ranitidine (150 mg twice daily) [increases gastric pH]	Cmax and AUC τ of voriconazole ↔	No dose adjustment required
Flucloxacillin [CYP450 inducer]	Significant reduction in voriconazole plasma concentration has been reported.	If concomitant use of voriconazole with flucloxacillin cannot be avoided, potential loss of voriconazole efficacy should be monitored (e.g., via therapeutic drug monitoring); voriconazole dose increase may be required.

Special precautions for use.

Hypersensitivity

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

Duration of use

Vfend Rompharm should not be administered intravenously for longer than 6 months.

Cardiovascular system

Voriconazole is associated with QTc interval prolongation. Rare cases of torsades de pointes ventricular tachycardia have been reported in patients receiving voriconazole who had risk factors such as a history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant use of drugs that may predispose to 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 corrected as necessary before initiating and during treatment with voriconazole (see section "Dosage and administration"). A study in healthy volunteers evaluated the effect of single doses of voriconazole up to 4 times the standard daily dose on the QTc interval. In no subject did the QTc interval exceed the potentially clinically significant threshold of 500 ms (see section "Pharmacodynamics").

Infusion-related reactions

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

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 (particularly hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, have also been observed in patients without other identified risk factors. Liver function abnormalities were reversible and usually resolved after discontinuation of therapy (see section "Adverse reactions").

Liver function monitoring

Patients receiving Vfend Rompharm should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (particularly measurement of 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 continued treatment is justified based on a risk-benefit assessment (see section "Dosage and administration"), monitoring frequency may be reduced to once monthly in the absence of changes in liver test results.

If liver test results show significant elevation, Vfend Rompharm should be discontinued, except when medical evaluation of the risk-benefit ratio supports continued use.

Liver function monitoring is required in both children and adults.

Serious skin reactions

Photosensitivity. Use of Vfend Rompharm has been additionally associated with photosensitivity reactions such as freckles, lentigo, actinic keratosis, and pseudoporphyria. There is a potential increased risk of skin reactions/toxicity with concomitant use of photosensitizing agents (e.g., methotrexate). All patients, including children, should avoid direct sunlight exposure, wear protective clothing, and use a high-protection sunscreen (SPF) during treatment with Vfend Rompharm.

Squamous cell carcinoma of the skin (SCC). Among patients with documented squamous cell carcinoma of the skin (including cutaneous SCC or Bowen’s disease), some had prior history of photosensitivity reactions. In case of photosensitivity reactions, multidisciplinary physician consultations should be conducted, treatment with Vfend Rompharm should be discontinued, alternative antifungal agents should be considered, and the patient should be referred to a dermatologist. If treatment with Vfend Rompharm is continued, the patient should be systematically and regularly examined by a dermatologist for early detection and treatment of potential precancerous lesions. If precancerous skin lesions or squamous cell carcinoma are detected, use of Vfend Rompharm must be discontinued (see section "Long-term therapy" 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 syndrome), have been reported during voriconazole use, which may be life-threatening or fatal. Patients presenting with rash should be closely monitored, and Vfend Rompharm should be discontinued if signs of disease progression occur.

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 CYP3A4 metabolism 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 voriconazole treatment (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be instructed to seek immediate medical attention if symptoms and signs of Cushing’s syndrome or adrenal insufficiency develop.

Long-term therapy

Long-term use of the drug (for treatment or prophylaxis) beyond 180 days (6 months) requires careful benefit-risk assessment. In addition, physicians should consider reducing the dose of Vfend Rompharm (see sections "Dosage and administration" and "Pharmacodynamics").

Cases of squamous cell carcinoma of the skin (SCC) (including cutaneous SCC or Bowen’s disease) have been reported in association with long-term use of Vfend Rompharm.

In patients who have undergone transplant surgery, non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed. If skeletal pain develops and radiological findings suggest periostitis, multidisciplinary physician consultations should be conducted and discontinuation of Vfend Rompharm should be considered.

Ocular adverse reactions

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

Renal adverse reactions

Acute renal failure has been reported in patients with severe underlying conditions receiving voriconazole. Renal function may decrease in patients receiving voriconazole concomitantly with nephrotoxic medicinal products and/or underlying conditions (see section “Adverse reactions”).

Renal function monitoring

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

Pancreatic function monitoring

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

Children

The safety and efficacy of voriconazole in children under 2 years of age have not been established (see sections "Adverse reactions" and "Pharmacodynamics"). Voriconazole is recommended for use in children aged 2 years and older. In children, elevated liver enzymes have been observed more frequently (see section "Adverse reactions"). Liver function monitoring is required in 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. Enhanced sun protection measures are required if SCC progression occurs in this patient group. Children exhibiting signs of photoaging, such as freckles or lentigo, should be monitored by a dermatologist and avoid sun exposure even after discontinuation of the drug.

Prevention.

If treatment-related adverse reactions occur (hepatotoxicity, severe skin reactions including photosensitivity and SCC, severe or prolonged visual disturbances, or 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 when phenytoin and voriconazole are used concomitantly. 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 and efavirenz are used concomitantly, the voriconazole dose should be increased to 400 mg every 12 hours, and the efavirenz dose should be reduced to 300 mg every 24 hours (see sections "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, frequent 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 close 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 adverse reactions associated with rifabutin (such as uveitis) is recommended when voriconazole and rifabutin are used concomitantly. 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 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 prolongation, is recommended when methadone and voriconazole are used concomitantly, as methadone levels increase with concomitant voriconazole use. Dose reduction of methadone may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Short-acting opioids (CYP3A4 substrates)

When alfentanil, fentanyl, and other 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"). Close monitoring of opioid-related adverse reactions (including prolonged monitoring of respiratory function) may be necessary, as the half-life of alfentanil is prolonged fourfold when co-administered with voriconazole, and study data show that concomitant use of fentanyl and voriconazole increases the mean AUC0–∞ of fentanyl.

Long-acting opioids (CYP3A4 substrates)

When long-acting opioids and voriconazole are used concomitantly, consider reducing the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone). Close 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").

Excipients

Sodium. This medicinal product contains 221 mg of sodium per vial, equivalent to 11% of the WHO recommended maximum daily intake of sodium—2 g per day for adults.

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

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

Use during pregnancy or breastfeeding.

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

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

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

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

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

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

Ability to affect reaction speed when driving or operating machinery.

Vfend Rompharm has a moderate effect on the ability to drive and operate machinery. Use of the medicinal product may cause reversible visual disturbances, including blurred vision, altered/enhanced visual perception, and/or photophobia. Patients experiencing such symptoms should avoid potentially hazardous activities, such as driving vehicles or operating machinery.

Dosage and Administration

Before starting treatment with Voriconazole Rompharm 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").

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

Treatment

Adults

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

To achieve plasma concentrations close to steady-state on the first day of treatment, therapy with Voriconazole Rompharm should be initiated with appropriate loading doses administered either orally or intravenously. Due to the high bioavailability of Voriconazole Rompharm after oral administration (96%; see section "Pharmacokinetics"), the route of administration may be switched between intravenous and oral, depending on clinical indications.

Detailed dosage recommendations are provided in the table:

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

* Oral formulations of voriconazole are available from other manufacturers.

** Including patients aged 15 years and older.

Duration of treatment. Treatment duration should be as short as possible, depending on the clinical and mycological response of the patient. If treatment longer than 180 days (6 months) is required, a careful benefit-risk assessment should be performed (see section "Dosage and Administration" 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 use of the medicinal product for prophylaxis, see below.

Children (from 2 to <12 years) and adolescents with low body weight (from 12 to 14 years and <50 kg)

The recommended dosing regimen is as follows:

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

* Oral formulations of voriconazole are available from other manufacturers.

Note. Based on population pharmacokinetic analysis in 112 immunocompromised children aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.

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

All other adolescents (12 to 14 years of age and ≥ 50 kg; 15 to 17 years of age regardless of body weight)

Voriconazole should be administered as in adults.

Dose adjustment (children [2 to <12 years] and adolescents with low body weight [12 to 14 years and <50 kg])

If the patient's response to treatment is inadequate, the dose may be increased by 1 mg/kg. If the patient cannot tolerate treatment, reduce the dose by 1 mg/kg.

Use in children aged 2 to <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 continued for up to 180 days after transplantation only in cases of ongoing immunosuppression or graft-versus-host disease (GvHD) (see section "Pharmacological properties").

Dosing

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups.

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 precautions" and "Pharmacological properties").

Treatment and prophylaxis

Dose adjustment

Dose adjustment in the absence of efficacy or in case of treatment-related adverse events is not recommended during prophylactic use.

If treatment-related adverse reactions occur, consider discontinuing voriconazole and initiating alternative antifungal agents (see sections "Special precautions" and "Adverse reactions").

Dose adjustment when used concomitantly 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 precautions" 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 precautions" and "Interaction with other medicinal products and other forms of interaction").

Geriatric patients

No dose adjustment is necessary 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 when the benefit of intravenous voriconazole outweighs the risks. In such cases, careful monitoring of serum creatinine levels is required. If serum creatinine increases, consider switching the route of administration of voriconazole 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 require dose adjustment.

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, but the maintenance dose should be halved (see section "Pharmacokinetics").

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

Information on the safety of voriconazole in patients with abnormalities in liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], and total bilirubin more than 5 times the upper limit of normal) is limited.

Voriconazole use has been associated with elevated liver function tests and clinical signs of liver injury such as jaundice; therefore, the drug should be used in patients with severe hepatic dysfunction only when benefit outweighs potential risk. Patients with severe hepatic dysfunction should be closely monitored for toxic effects of the drug (see section "Adverse reactions").

Method of administration

Prior to intravenous infusion, the medicinal product must be reconstituted and diluted. Voriconazole Rompharm 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 injections or in 19 ml of 9 mg/ml (0.9%) sodium chloride solution for infusion. Do not use the vial of Voriconazole Rompharm if the solvent is not 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 mechanical particles should be administered.

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

Required volumes of Voriconazole Rompharm concentrate (10 mg/ml)

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

The reconstituted solution may be diluted with:

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

Compatibility of voriconazole with other diluents is unknown.

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

Children.

The safety and efficacy of voriconazole in children under 2 years of age have not been established. Current available data are presented in the sections "Side Effects" and "Pharmacological Properties", but dosage recommendations cannot be provided.

Overdose.

During clinical trials, three cases of accidental overdose were reported. All three cases occurred in children who received intravenous voriconazole at a dose nearly five times higher than recommended. The only reported adverse reaction was photophobia lasting 10 minutes.

There is no known antidote for voriconazole.

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

In case of overdose, hemodialysis may enhance the elimination of voriconazole and sodium β-cyclodextrin sulfobutyl ether from the body.

Adverse Reactions

Short description of the safety profile

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 population 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, liver function test abnormalities, respiratory disorders, and abdominal pain.

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

Summary list 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 studies (1603) and prophylaxis studies (270).

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

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

Adverse reactions observed in patients receiving voriconazole

System Organ Classes	Very common	Common	Uncommon	Rare	Frequency not known
Infections and infestations		sinusitis	pseudomembranous colitis
Benign, malignant and unspecified neoplasms (including cysts and polyps)		Squamous cell carcinoma of the skin (including SCC in situ of the skin or Bowen’s disease)*, **
Blood and lymphatic system disorders		agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anemia	bone marrow failure, lymphadenopathy, eosinophilia	disseminated intravascular coagulation
Immune system disorders			hypersensitivity	anaphylactoid reaction
Endocrine disorders			adrenal insufficiency, hypothyroidism	hyperthyroidism
Metabolism and nutrition disorders	peripheral edema	hypoglycemia, hypokalemia, hyponatremia
Psychiatric disorders		depression, hallucinations, anxiety, insomnia, agitation, confusion
Nervous system disorders	headache	seizures, syncope, tremor, hypertension3, paresthesia, somnolence, dizziness	brain edema, encephalopathy4, extrapyramidal disorder5, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia	hepatic encephalopathy, Guillain-Barré syndrome, nystagmus
Eye disorders	vision disorders6	retinal hemorrhage	optic nerve disorders7, optic disc edema8, oculogyric crisis, diplopia, scleritis, blepharitis	optic nerve atrophy, corneal clouding
Ear and labyrinth disorders			hearing impairment, vertigo, tinnitus
Cardiac disorders		supraventricular arrhythmia, tachycardia, bradycardia	ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, prolonged QT interval on electrocardiogram, supraventricular tachycardia	ventricular tachycardia of the torsade de pointes type, complete atrioventricular block, bundle branch block, nodal rhythm
Vascular disorders		hypotension, phlebitis	thrombophlebitis, lymphangitis
Respiratory, thoracic and mediastinal disorders	respiratory distress9	acute respiratory distress syndrome, pulmonary edema
Gastrointestinal disorders	diarrhea, vomiting, abdominal pain, nausea	cheilitis, dyspepsia, constipation, gingivitis	peritonitis, pancreatitis, tongue edema, duodenitis, gastroenteritis, glossitis
Hepatobiliary disorders	liver function test abnormalities	jaundice, cholestatic jaundice, hepatitis10	hepatic failure, hepatomegaly, cholecystitis, cholelithiasis
Skin and subcutaneous tissue disorders	rash	exfoliative dermatitis, alopecia, maculopapular rash, pruritus, erythema, photosensitivity**	Stevens-Johnson syndrome8, purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema	toxic epidermal necrolysis8, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)8, angioneurotic edema, actinic keratosis*, polymorphic pseudoporphyria, erythema, psoriasis, drug eruption	cutaneous lupus erythematosus*, freckles*, lentigo*
Musculoskeletal and connective tissue disorders		back pain	arthritis, periostitis*,**
Renal and urinary disorders		acute renal failure, hematuria	renal tubular necrosis, proteinuria, nephritis
General disorders and administration site conditions	fever	chest pain, facial edema11, asthenia, chills	infusion site reaction, influenza-like illness
Investigations		increased blood creatinine	increased blood urea, increased blood cholesterol

• Adverse reactions identified after marketing of the medicinal product.

** The frequency category is based on 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 section "Visual impairment" below.

7 After marketing of the medicinal product, prolonged optic neuritis has been reported (see section "Special precautions").

8 See section "Special precautions".

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 oral swelling.

Visual impairment

During clinical and therapeutic studies, visual impairment (particularly blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorders, presence of rainbow-colored halos in the visual field, night blindness, oscillopsia, photopsia, flickering scotoma, decreased visual acuity, visual brightness, visual field defects, floaters in the vitreous body, and xanthopsia) was very commonly observed with voriconazole use. This visual impairment was transient and fully reversible, and in most cases spontaneously resolved within 60 minutes; clinically significant long-term visual reactions were not observed. Symptoms tended to diminish with repeated administration of voriconazole. Cases of visual impairment were generally mild, rarely led to discontinuation of the medicinal product, and were not associated with prolonged residual effects. Visual impairment may be related to high plasma concentrations and/or doses of the medicinal product.

The mechanism of visual disturbances is unknown, although the medicinal product most likely affects the retina. Voriconazole administration caused a reduction in the amplitude of waves on electroretinogram (ERG) during a clinical study evaluating the effect of voriconazole on retinal function in healthy volunteers. ERG measures electrical potentials of the retina of the eye. Changes on ERG did not progress over 29 days of therapy and completely resolved after discontinuation of voriconazole.

After marketing of the medicinal product, prolonged adverse reactions affecting the visual organs have been reported; see section "Special precautions".

Skin reactions

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

Patients should be closely monitored for skin reactions, and if lesions progress, treatment with Voriconazole Rompharm should be discontinued. Cases of photosensitivity reactions such as freckling, lentigo, and actinic keratosis have been reported, particularly during prolonged use of the medicinal product (see section "Special precautions").

Cases of cutaneous squamous cell carcinoma (including cutaneous SCC 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”).

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 and prophylaxis. Abnormal liver function test results may be associated with high plasma concentrations and/or doses of the medicinal product. Most abnormal liver function test results resolved during continued treatment without dose adjustment or after dose adjustment, including discontinuation of the medicinal product.

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

Reactions related to intravenous infusion

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

Prophylaxis

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

Children

The safety of voriconazole was evaluated in 288 children aged 2–12 years (169) and aged 12–18 years (119), who received voriconazole for prophylaxis (183) and treatment (105) in clinical studies. The safety of voriconazole was also evaluated in 158 children aged 2–12 years within compassionate-use programs. Overall, the safety profile of voriconazole in children was similar to that in adults. However, elevated liver enzymes were more frequently observed in children compared to adults (incidence of transaminase elevations was 14.2% in children versus 5.3% in adults). Post-marketing experience suggests that the frequency of skin reactions (particularly erythema) may be somewhat higher in children than in adults. In 22 patients under 2 years of age receiving voriconazole within compassionate-use programs, the following adverse reactions (causal relationship with voriconazole not excluded) were observed: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), elevated blood bilirubin (1), elevated liver enzymes (1), rash (1), and optic disc edema (1). Pancreatitis in children has also been reported during the post-marketing period.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C.

Reconstituted solution: chemical and physical in-use stability has been demonstrated for 24 hours at 2–8 °C.

Diluted infusion solution: chemical and physical in-use stability has been demonstrated for 48 hours at 2–8 °C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the end user.

Incompatibilities.

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

Blood products and short-term infusions of concentrated electrolyte solutions

Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to initiating voriconazole therapy (see sections "Dosage and administration" and "Special precautions"). Voriconazole Rompharm must not be administered simultaneously with any blood product or any short-term infusion of concentrated electrolyte solutions, even if both infusions are administered through separate lines.

Total parenteral nutrition.

Total parenteral nutrition does not need to be discontinued during administration of Voriconazole Rompharm, but it should be administered through a separate infusion line. When administering via a multi-lumen catheter, total parenteral nutrition should be administered through a separate port, not through the port used for Voriconazole Rompharm infusion. Voriconazole Rompharm 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 in a vial, 1 vial in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

K.T. ROMPHARM COMPANY S.R.L.

Manufacturer’s address and location of its business operations.

Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.