Voriconazole-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORICONAZOLE-VISTA (VORICONAZOLE-VISTA)

Composition:

Active substance: voriconazole;

One film-coated tablet contains 50 mg or 200 mg of voriconazole;

Excipients: lactose monohydrate; povidone K 29-32; sodium croscarmellose; pregelatinized starch; magnesium stearate; purified water;

Coating components: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin; purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg: white or almost white, round, biconvex, film-coated tablets, engraved with "V9CN" on one side and "50" on the other;

200 mg: white or almost white, oval, biconvex, film-coated tablets, engraved with "V9CN" on one side and "200" on the other.

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

Pharmacokinetics/pharmacodynamics.

In 10 therapeutic studies, median average and maximum plasma concentrations in patients were 2425 ng/mL (interquartile range 1193–4380 ng/mL) and 3742 ng/mL (interquartile range 2027–6302 ng/mL), respectively. A positive relationship between average, maximum, or minimum plasma concentrations of voriconazole and efficacy was not established during therapeutic studies and was not demonstrated in prophylaxis trials.

Pharmacokinetic/pharmacodynamic analysis of clinical trials revealed a positive association between plasma voriconazole concentrations and abnormalities in liver function tests and visual disturbances. Dose adjustment was not studied in prophylaxis trials.

Clinical efficacy and safety.

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

Clinical efficacy (defined as partial or complete response) of voriconazole has been demonstrated against various Aspergillus species, including A. flavus, A. fumigatus, A. terreus, A. niger, 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, S. prolificans; and various Fusarium species.

Other fungal infections against which voriconazole is effective (often with partial or complete response) 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 of 0.05–2 µg/mL. In vitro activity of the drug has also been demonstrated against various Curvularia species and various Sporothrix species, although the clinical significance of this activity has not yet been established.

Susceptibility breakpoints.

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

The most common species causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei, all of which have a minimum inhibitory concentration (MIC) of voriconazole less than 1 mg/L. However, in vitro activity of voriconazole against different Candida species is not uniform. In particular, for C. glabrata, the MIC of voriconazole is proportionally higher for fluconazole-resistant strains than for fluconazole-susceptible strains. Therefore, every effort should be made to identify Candida to the species level. If results of antifungal susceptibility testing of the pathogen are available, MIC data may be interpreted using the susceptibility breakpoint criteria established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST susceptibility breakpoints

Table 1

Species of Candida and Aspergillus	Minimum Inhibitory Concentration (MIC) breakpoints (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 yet been reported. Identification of any such strain and testing its susceptibility to antifungal agents should be repeated, and if the result is confirmed, the strain should be referred to a reference laboratory. The strain should be considered resistant until clinical evidence is obtained from confirmed isolates with MICs above the current resistance breakpoint. For infections caused by the species listed below, a clinical response rate of 76% was achieved when MICs were below 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 primarily established based on PK/PD data and do not depend on the MIC distribution of a specific Candida species. They should be used only for microorganisms lacking their own species-specific breakpoints. 4 The technical uncertainty zone (TUZ) is 2. Report as "R" with the following note: "In certain clinical situations (non-invasive forms of infection), voriconazole may be used provided adequate exposure is ensured." 5 ECOFF for these species is generally one two-fold dilution higher than for A. fumigatus. 6 Non-species-related breakpoints have not been established.

Clinical experience. In this section, a favorable outcome of treatment with the medicinal product 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 standard amphotericin B as first-line therapy for acute invasive aspergillosis were demonstrated in an open-label, randomized, multicenter study involving 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours for 7 days. The route of administration could be switched to oral dosing of 200 mg every 12 hours. The median duration of intravenous voriconazole therapy was 10 days (2–85 days). After intravenous treatment, the median duration of oral voriconazole therapy was 76 days (2–232 days). A favorable overall response (complete or partial resolution of all associated symptoms and radiographic/bronchoscopic abnormalities present prior to treatment initiation) 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 agent, and clinically and statistically significant advantages of voriconazole were demonstrated both in terms of time to death and time to drug discontinuation due to toxicity. This study confirmed the results of a previous prospective study, which showed a positive outcome of the drug in patients with risk factors for poor prognosis, including graft-versus-host reaction and particularly cerebral infections (typically associated with 100% mortality). In these studies, the drug was investigated for the treatment of sinus aspergillosis, cerebral, pulmonary, and disseminated aspergillosis in patients after bone marrow and parenchymal organ transplantation, as well as in patients with hematological malignancies, solid tumors, and AIDS.

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

In a secondary analysis using assessments by the Independent Data Monitoring 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 amphotericin B followed by fluconazole were 65% and 71%, respectively.

The rates of favorable treatment outcome as assessed by investigators at each of these evaluable time points are presented in Table 2.

Table 2

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

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

Infections caused by various Scedosporium and Fusarium species. Efficacy of voriconazole against the following rare pathogenic fungi has been demonstrated:

• Scedosporium species: favorable response to voriconazole therapy was observed in 16 out of 28 patients infected with S. apiospermum (6 with complete response, 10 with partial response) and in 2 out of 7 patients infected with S. prolificans (partial response in both). Additionally, 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.

Most patients who received voriconazole for the treatment of the aforementioned rare fungal infections had either intolerance or resistance to previously administered antifungal agents.

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

Table 3

Study endpoints	Voriconazole N=224	Itraconazole N=241	Difference in proportions and 95% confidence interval (CI)	P-value
Effectiveness on day 180*	109 (48.7%)	80 (33.2%)	16.4% (7.7%, 25.1%)**	0.0002**
Effectiveness on day 100	121 (54.0%)	96 (39.8%)	15.4% (6.6%, 24.2%)**	0.0006**
Duration of 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 efficacy endpoint of the study.

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

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

Acute Myeloid Leukemia

Table 4

Criteria for effectiveness	Voriconazole (N=98)	Itraconazole (N=109)	Difference in ratios and 95% confidence interval (CI)
Occurrence of invasive fungal infection – day 180	1 (1.0%)	2 (1.8%)	0.8% (–4.0%, 2.4%) **
Effectiveness on day 180*	55 (56.1%)	45 (41.3%)	14.7% (1.7%, 27.7%)***

* Primary efficacy endpoint of the study.

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

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

Myeloablative conditioning regimen

Table 5

Criteria for effectiveness	Voriconazole (N=125)	Itraconazole (N=143)	Difference in ratios and 95% confidence interval (CI)
Occurrence of invasive fungal infection – day 180	2 (1.6%)	3 (2.1%)	0.5% (–3.7%, 2.7%) **
Effectiveness on day 180*	70 (56.0%)	53 (37.1%)	20.1% (8.5%, 31.7%)***

* Primary efficacy endpoint of the study.

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

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

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

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

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

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

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

Pharmacokinetics.

General pharmacokinetic characteristics.

Voriconazole pharmacokinetics were studied in healthy volunteers, special populations, and patients. After oral administration of 200 mg or 300 mg twice daily for 14 days in patients at increased risk of developing aspergillosis (mainly patients with malignancies of lymphatic and hematopoietic tissues), the pharmacokinetic parameters evaluated—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 its extensive metabolism. As the dose increases, exposure increases to a greater extent than proportionally. It was 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 maintenance dose of 200 mg (or 100 mg for patients with body weight less than 40 kg) achieves exposure equivalent to 3 mg/kg administered intravenously. An oral maintenance dose of 300 mg (or 150 mg for patients with body weight less than 40 kg) achieves exposure equivalent to 4 mg/kg administered intravenously. After administration of loading doses of voriconazole either intravenously or orally, plasma concentrations close to steady-state are achieved within the first 24 hours of therapy. If a loading dose regimen is not used, with repeated administration of voriconazole twice daily, accumulation to steady-state plasma concentrations occurs by day 6 in most patients.

Absorption.

Voriconazole is rapidly and almost completely absorbed after oral administration, reaching maximum plasma concentration (Cmax) within 1–2 hours after dosing. Absolute bioavailability of voriconazole after oral administration is 96 %. When voriconazole was administered repeatedly with a high-fat meal, Cmax and AUCτ decreased by 34 % and 24 %, respectively. Changes in gastric pH do not affect voriconazole absorption.

Distribution.

The volume of distribution at steady-state for voriconazole is estimated at 4.6 L/kg, indicating extensive tissue distribution. Plasma protein binding of voriconazole is approximately 58 %.

Voriconazole was detected in measurable concentrations in all cerebrospinal fluid samples obtained from 8 patients within a compassionate-use program.

Metabolism.

In vitro studies demonstrated that voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4.

Voriconazole exhibits high inter-subject pharmacokinetic variability. In vivo studies have shown that CYP2C19 plays a significant role in voriconazole metabolism. This enzyme exhibits genetic polymorphism. For example, 15–20 % of patients of Mongoloid race are expected to be slow metabolizers of this drug. Among Caucasian and Negroid populations, the proportion of slow metabolizers is 3–5 %. Studies conducted in healthy Caucasian and Japanese volunteers demonstrated that in "poor metabolizers" of voriconazole, drug exposure (AUCτ) is on average 4 times higher than in the comparator group of homozygous "extensive metabolizers." Heterozygous "intermediate metabolizers" have on average 2 times higher drug exposure than the comparator group of homozygous "extensive metabolizers." The main metabolite of voriconazole is the N-oxide, which accounts for 72 % of the total radio-labeled metabolites circulating in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Excretion.

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

After administration of radiolabeled voriconazole, approximately 80 % of radioactivity was recovered in urine following multiple intravenous doses and 83 % following multiple oral doses. The majority (> 94 %) of radioactive substances were eliminated within the first 96 hours after both oral and intravenous administration. The terminal half-life of voriconazole is dose-dependent and is approximately 6 hours after an oral 200 mg dose. Due to non-linear pharmacokinetics, terminal half-life is not used to assess accumulation or elimination of voriconazole.

Pharmacokinetics in special patient populations.

Gender.

In a multiple-dose oral study, Cmax and AUCτ levels in healthy young women were 83 % and 113 % higher, respectively, than in healthy young men (18–45 years). In this same study, no statistically significant differences in Cmax and AUCτ levels were observed between healthy elderly men and women (≥ 65 years).

In the clinical program, dose adjustment was not performed based on gender. Safety profiles and plasma concentrations of the drug in women and men were similar. Therefore, dose adjustment based on gender is not necessary.

Elderly patients.

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

In therapeutic studies, dose adjustment was not performed based on age. A relationship between plasma concentration and patient age was observed. Safety profiles of voriconazole in younger and elderly patients were similar; therefore, dose adjustment in elderly patients is not required.

Pediatric patients.

This patient population exhibited greater inter-subject 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. The expected total exposure in children after intravenous maintenance doses of 4 and 8 mg/kg twice daily was comparable to AUCτ in adults after intravenous maintenance doses of 3 and 4 mg/kg twice daily, respectively. The expected total exposure in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults after 200 mg orally twice daily. Exposure after an intravenous dose of 8 mg/kg is expected to be twice that after an oral dose of 9 mg/kg.

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

Exposure to voriconazole in most adolescents was comparable to that in adults at the same dosing regimen. However, lower exposure was observed in some younger adolescents with low body weight compared to adults. It is possible that voriconazole is metabolized in these patients via a pathway more similar to that in children than in adults. Based on pharmacokinetic analysis, adolescents aged 12–14 years with body weight less than 50 kg should receive pediatric dosing.

Renal impairment.

In a single-dose oral study (200 mg) involving patients with normal liver function and patients with mild (creatinine clearance 41–60 mL/min) to severe (creatinine clearance < 20 mL/min) renal impairment, renal impairment did not significantly affect the pharmacokinetics of voriconazole. Plasma protein binding of voriconazole was similar across patients with varying degrees of renal impairment.

Hepatic impairment.

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

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 not available.

Clinical characteristics.

Indications.

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

Voriconazole is indicated in adults and children from 2 years of age for the treatment of:

• invasive aspergillosis;
• candidaemia, not associated with neutropenia;
• serious invasive infections caused by Candida (including C. krusei) resistant to fluconazole;
• severe fungal infections caused by Scedosporium species and Fusarium species.

For patients with progressive or potentially life-threatening infections, Voriconazole-Vista should be used as initial therapy.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, or quinidine or ivabradine, as increased plasma concentrations of these medicinal products may lead to QTc interval prolongation and, rarely, to the development of ventricular tachycardia of the torsades de pointes type (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with rifampicin, carbamazepine, and phenobarbital, as these medicinal products can significantly reduce voriconazole plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of standard doses of voriconazole with efavirenz at a dose of 400 mg per day or higher, as administration of efavirenz at these doses significantly reduces voriconazole plasma concentrations in healthy volunteers. Voriconazole also significantly increases efavirenz plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"; for use of lower doses, see section "Special precautions for use").
• Concomitant use with high-dose ritonavir (400 mg or more twice daily), as administration of such doses of ritonavir leads to a significant reduction in voriconazole plasma concentrations in healthy volunteers (for use of lower ritonavir doses, see section "Special precautions for use").
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as increased plasma concentrations of these medicinal products may lead to ergotism (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with St John’s wort (Hypericum perforatum) preparations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with venetoclax at the initiation of treatment and during the dose-titration phase of venetoclax, as voriconazole is likely to significantly increase venetoclax plasma concentrations and increase the risk of tumour lysis syndrome (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Voriconazole is metabolized by and inhibits the activity of cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. There is also a potential for voriconazole to increase plasma concentrations of substances metabolized by these CYP450 isoenzymes; this is particularly relevant for substances metabolized by CYP3A4, as voriconazole is a strong inhibitor of CYP3A4, although the extent of AUC increase depends on the substrate (see table below).

Drug interaction studies were conducted in healthy male volunteers who received multiple oral doses of voriconazole 200 mg twice daily to achieve steady state. These results are relevant to other populations and routes of administration.

Voriconazole should be used with caution in patients who are concurrently taking a medicinal product known to prolong the QTc interval. If there is also a likelihood that voriconazole will increase plasma concentrations of substances metabolized by CYP3A4 isoenzymes (e.g., certain antihistamines, quinidine, cisapride, pimozide, and ivabradine), concomitant use is contraindicated.

Examples of voriconazole interactions with other medicinal products are presented in Table 6 (once daily is indicated as "QD", twice daily as "BID", three times daily as "TID", and not determined as "ND"). The notation for each pharmacokinetic parameter is based on the 90% confidence interval of the ratio of geometric means within (↔), below (↓), or above (↑) the 80–125% range. An asterisk (*) indicates bidirectional interaction. AUCτ, AUQt, and AUC0-∞ refer to the area under the concentration-time curve over the dosing interval, from time "0" to a specified time point, and from time "0" to infinity, respectively.

The interactions listed in the table below are presented in the following order: contraindicated, those requiring dose adjustment and careful clinical and/or biological monitoring, and those without significant pharmacokinetic interaction but which may have clinical relevance within this therapeutic range.

Table 6

Medicinal product [Mechanism of interaction]	Interaction Geometric mean changes (%)	Recommendations for concomitant use
Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine [CYP3A4 substrates]	Although interaction has not been studied, increased plasma concentrations of these medicinal products may lead to QTc prolongation and rare cases of torsades de pointes ventricular tachycardia.	Contraindicated (see section "Contraindications")
Carbamazepine and long-acting barbiturates (e.g. phenobarbital, mephobarbital) [potent CYP450 inducers]	Although interaction has not been studied, carbamazepine and long-acting barbiturates may significantly reduce voriconazole plasma concentrations.	Contraindicated (see section "Contraindications")
Efavirenz (non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; inhibitor and substrate of CYP3A4] Efavirenz 400 mg once daily with voriconazole 200 mg twice daily Efavirenz 300 mg once daily with voriconazole 400 mg twice daily	Efavirenz Cmax ↑ 38 % Efavirenz AUCτ ↑ 44 % Voriconazole Cmax ↓ 61 % Voriconazole AUCτ ↓ 77 % Compared to efavirenz 600 mg once daily, Efavirenz Cmax ↔ Efavirenz AUCτ ↑ 17 % Compared to voriconazole 200 mg twice daily, Voriconazole Cmax ↑ 23 % Voriconazole AUCτ ↓ 7 %	Concomitant use of standard doses of voriconazole with efavirenz 400 mg once daily or higher is contraindicated (see section "Contraindications") Voriconazole may be used concomitantly with efavirenz provided the maintenance dose of voriconazole is increased to 400 mg twice daily and the dose of efavirenz is reduced to 300 mg once daily. After discontinuation of voriconazole therapy, the original efavirenz dose should be restored (see section "Dosage and administration", "Special instructions").
Ergot alkaloids (e.g. ergotamine and dihydroergotamine) [CYP3A4 substrates]	Although interaction has not been studied, voriconazole may increase plasma concentrations of ergot alkaloids and lead to ergotism.	Contraindicated (see section "Contraindications")
Rifabutin [potent CYP450 inducer] 300 mg once daily 300 mg once daily with voriconazole 350 mg twice daily 300 mg once daily with voriconazole 400 mg twice daily	Voriconazole Cmax ↓ 69 % Voriconazole AUCτ ↓ 78 % Compared to voriconazole 200 mg twice daily, Voriconazole Cmax ↓ 4 % Voriconazole AUCτ ↓ 32 % Rifabutin Cmax ↑ 195 % Rifabutin AUCτ ↑ 331 % Compared to voriconazole 200 mg twice daily, Voriconazole Cmax ↑ 104 % Voriconazole AUCτ ↑ 87 %	Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk. The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients weighing less than 40 kg) (see section "Dosage and administration"). When rifabutin is used concomitantly with voriconazole, careful monitoring of complete blood count and rifabutin-related adverse reactions (such as uveitis) is recommended.
Rifampicin 600 mg once daily [potent CYP450 inducer]	Voriconazole Cmax ↓ 93 % Voriconazole AUCτ ↓ 96 %	Contraindicated (see section "Contraindications")
Ritonavir (protease inhibitor). [potent CYP450 inducer; inhibitor and substrate of CYP3A4] High dose 400 mg twice daily. Low dose 100 mg twice daily.	Ritonavir Cmax and AUCτ ↔ Voriconazole Cmax ↓ 66 % Voriconazole AUCτ ↓ 82 % Ritonavir Cmax ↓ 25 % Ritonavir AUCτ ↓ 13 % Voriconazole Cmax ↓ 24 % Voriconazole AUCτ ↓ 39 %	Concomitant use of voriconazole with high-dose ritonavir (400 mg or higher twice daily) is contraindicated (see section "Contraindications"). Concomitant use of voriconazole with low-dose ritonavir (100 mg twice daily) should be avoided unless benefit outweighs risk.
St. John's wort [CYP450 inducer; P-gp inducer] 300 mg three times daily with single dose voriconazole 400 mg	In an independent published study Voriconazole AUC0-∞ ↓ 59 %	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 of venetoclax therapy and during the dose titration phase (see section "Contraindications"). Dose reduction of venetoclax is required as indicated in the venetoclax product information during stable daily dosing; careful monitoring for signs of toxicity is recommended.
Everolimus [CYP3A4 substrate, P-gp substrate]	Although interaction has not been studied, voriconazole may cause a significant increase in everolimus plasma concentrations.	Concomitant use of voriconazole with everolimus is not recommended due to expected significant increase in everolimus concentration.
Lurasidone [CYP3A4 substrate]	Although voriconazole has not been studied, it may significantly increase lurasidone plasma concentrations.	Contraindicated (see section Contraindications)
Naloxegol (CYP3A4 substrate)	Although not studied, voriconazole is likely to cause a significant increase in naloxegol plasma concentrations	Concomitant use of voriconazole and naloxegol is not recommended due to insufficient data to provide clear dosing guidance in such a situation (see section "Special instructions").
Fluconazole 200 mg once daily [CYP2C9, CYP2C19 and CYP3A4 inhibitor]	Voriconazole Cmax ↑ 57 % Voriconazole AUCτ ↑ 79 % Fluconazole Cmax not determined Fluconazole AUCτ not determined	Dose reduction and/or frequency adjustment of voriconazole and fluconazole to eliminate these effects has not been studied. Monitoring for adverse reactions associated with voriconazole is recommended if voriconazole is administered after fluconazole.
Phenytoin [CYP2C9 substrate and potent CYP450 inducer] 300 mg once daily 300 mg once daily with voriconazole 400 mg twice daily	Voriconazole Cmax ↓ 49 % Voriconazole AUCτ ↓ 69 % Phenytoin Cmax ↑ 67 % Phenytoin AUCτ ↑ 81 % Compared to voriconazole 200 mg twice daily Voriconazole Cmax ↑ 34 % Voriconazole AUCτ ↑ 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 weighing less than 40 kg)
Flucloxacillin [CYP450 inducer]	Significant reduction in voriconazole plasma concentration has been reported.	If concomitant use of voriconazole with flucloxacillin cannot be avoided, monitoring for potential loss of voriconazole efficacy (e.g. via therapeutic drug monitoring) is recommended; dose increase of voriconazole may be required.
Glasdegib [CYP3A4 substrates]	Although voriconazole has not been studied, it may increase glasdegib plasma concentrations and risk of QTc prolongation.	If concomitant use cannot be avoided, frequent ECG monitoring is recommended (see section "Special instructions").
Tyrosine kinase inhibitors (including but not limited to: axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) [CYP3A4 substrates]	Although voriconazole has not been studied, it 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 instructions").
Letermovir (CYP2C9 and CYP2C19 inducer)	Voriconazole Cmax ↓ 39 % Voriconazole AUC0-12 ↓ 44 % Voriconazole C12 ↓ 51 %	If voriconazole must be used with letermovir, monitor for reduced efficacy of voriconazole.
Anticoagulants Warfarin single dose 30 mg with voriconazole 300 mg twice daily [CYP2C9 substrate] Other oral coumarins (e.g. phenprocoumon, acenocoumarol) [CYP2C9 and CYP3A4 substrates]	Prothrombin time increased approximately two-fold. Although interaction has not been studied, voriconazole may increase plasma concentrations of coumarins, leading to increased prothrombin time.	Close monitoring of prothrombin time or other appropriate anticoagulation tests and appropriate adjustment of anticoagulant dose are recommended.
Ivacaftor (CYP3A4 substrate).	Interaction between voriconazole and ivacaftor has not been studied, but increased plasma concentration of ivacaftor is possible, which may increase the risk of adverse reactions.	Dose reduction of ivacaftor is recommended.
Benzodiazepines (e.g. midazolam, triazolam, alprazolam) [CYP3A4 substrates]	Although clinical interaction has not been studied, voriconazole may increase plasma concentrations of benzodiazepines metabolized by CYP3A4 and lead to prolonged sedative effect.	Consideration should be given to reducing benzodiazepine doses.
Tolvaptan (CYP3A substrate)	Interaction with voriconazole has not been studied, but it is likely that voriconazole significantly increases tolvaptan plasma concentrations	If concomitant use of voriconazole with tolvaptan is necessary, the dose of the latter should be reduced
Immunosuppressants [CYP3A4 substrates] Sirolimus single dose 2 mg Cyclosporine (in stable renal transplant recipients receiving long-term cyclosporine therapy) Tacrolimus single dose 0.1 mg/kg	In an independent published study Sirolimus Cmax ↑ 6.6-fold Sirolimus AUC0-∞ ↑ 11-fold Cyclosporine Cmax ↑ 13 % Cyclosporine AUCτ ↑ 70 % Tacrolimus Cmax ↑ 117 % Tacrolimus AUCt ↑ 221 %	Concomitant use of voriconazole and sirolimus is contraindicated. At initiation of voriconazole in patients already receiving cyclosporine, it is recommended to reduce the cyclosporine dose by half and closely monitor cyclosporine levels. Elevated cyclosporine levels have been associated with nephrotoxicity. Upon discontinuation of voriconazole, cyclosporine levels should be closely monitored and the dose increased if necessary. At initiation of voriconazole in patients already receiving tacrolimus, it is recommended to reduce the tacrolimus dose to one-third of the initial dose and closely monitor tacrolimus levels. Elevated tacrolimus levels have been associated with nephrotoxicity. Upon discontinuation of voriconazole, tacrolimus levels should be closely monitored and the dose increased if necessary.
Long-acting opioids [CYP3A4 substrates] Oxycodone single dose 10 mg	In an independent published study Oxycodone Cmax ↑ 1.7-fold Oxycodone AUC0-∞ ↑ 3.6-fold	Consideration should be given to reducing the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g. hydrocodone). Frequent monitoring for opioid-related adverse reactions may be required.
Methadone (32–100 mg once daily) [CYP3A4 substrate]	R-methadone (active) Cmax ↑ 31 % R-methadone (active) AUCτ ↑ 47 % S-methadone Cmax ↑ 65 % S-methadone AUCτ ↑ 103 %	Frequent monitoring for methadone-related adverse reactions and toxicity, including QT prolongation, is recommended. Dose reduction of methadone may be needed.
Non-steroidal anti-inflammatory drugs (NSAIDs) [CYP2C9 substrates] ibuprofen single dose 400 mg Diclofenac single dose 50 mg	S-ibuprofen Cmax ↑ 20 % S-ibuprofen AUC0-∞ ↑ 100 % Diclofenac Cmax ↑ 114 % Diclofenac AUC0-∞ ↑ 78 %	Frequent monitoring for development of NSAID-related adverse reactions and toxicity is recommended. Dose reduction of NSAIDs may be needed.
Omeprazole (40 mg once daily)* [CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]	Omeprazole Cmax ↑ 116 % Omeprazole AUCτ ↑ 280 % Voriconazole Cmax ↑ 15 % Voriconazole AUCτ ↑ 41 % Other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole, leading to increased plasma concentrations of these medicinal products.	Dose adjustment of voriconazole is not recommended. At initiation of voriconazole in patients already receiving omeprazole doses of 40 mg or higher, it is recommended to reduce the omeprazole dose by half.
Oral contraceptives* [CYP3A4 substrate; CYP2C19 inhibitor] Norethisterone/ethinylestradiol (1 mg/0.035 mg once daily)	Ethinylestradiol Cmax ↑ 36 % Ethinylestradiol AUCτ ↑ 61 % Norethisterone Cmax ↑ 15 % Norethisterone AUCτ ↑ 53 % Voriconazole Cmax ↑ 14 % Voriconazole AUCτ ↑ 46 %	Frequent monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended.
Short-acting opioids [CYP3A4 substrates] Alfentanil single dose 20 mcg/kg with concomitant naloxone Fentanyl single dose 5 mcg/kg	In an independent published study Alfentanil AUC0-∞ ↑ 6-fold In an independent published study Fentanyl AUC0-∞ ↑ 1.34-fold	Consideration should be given to reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g. sufentanil). Frequent monitoring for respiratory depression and opioid-related adverse reactions is recommended.
Statins (e.g. lovastatin) [CYP3A4 substrates]	Although clinical interaction has not been studied, voriconazole may increase plasma concentrations of statins metabolized by CYP3A4, potentially leading to rhabdomyolysis.	Consideration should be given to reducing the dose of statins.
Sulfonylureas (e.g. tolbutamide, glipizide, glyburide) [CYP2C9 substrates]	Although interaction has not been studied, voriconazole may increase plasma concentrations of sulfonylureas and cause hypoglycemia.	Close monitoring of blood glucose levels is recommended. Consideration should be given to reducing the dose of sulfonylureas.
Vinca alkaloids (e.g. vincristine and vinblastine) [CYP3A4 substrates]	Although interaction has not been studied, voriconazole may increase plasma concentrations of vinca alkaloids and lead to neurotoxicity.	Consideration should be given to reducing the dose of vinca alkaloids.
Other HIV protease inhibitors (e.g. saquinavir, amprenavir, nelfinavir)* [substrates and inhibitors of CYP3A4]	Not clinically studied. In vitro studies show that voriconazole may inhibit the metabolism of HIV protease inhibitors, and that voriconazole metabolism may also be inhibited by HIV protease inhibitors.	Close monitoring of patients for any signs of drug toxicity and/or lack of efficacy, and dose adjustment, are recommended.
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g. delavirdine, nevirapine)* [substrates, inhibitors of CYP3A4 or CYP450 inducers]	Not clinically studied. In vitro studies show that voriconazole metabolism may be inhibited by NNRTIs, and voriconazole may inhibit NNRTI metabolism. Data from efavirenz effects on voriconazole suggest that voriconazole metabolism may be induced by NNRTIs.	Close monitoring for drug toxicity and/or lack of efficacy, and dose adjustment, may be required.
Tretinoin [CYP3A4 substrate]	Although voriconazole has not been studied, it may increase tretinoin concentrations and 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 and increases gastric pH]	Voriconazole Cmax ↑ 18 % Voriconazole AUCτ ↑ 23 %	No dose adjustment required.
Digoxin 0.25 mg once daily [P-gp substrate]	Digoxin Cmax ↔ Digoxin AUCτ ↔	No dose adjustment required.
Indinavir 800 mg three times daily [CYP3A4 inhibitor and substrate]	Indinavir Cmax ↔ Indinavir AUCτ ↔ Voriconazole Cmax ↔ Voriconazole AUCτ ↔	No dose adjustment required.
Macrolide antibiotics Erythromycin 1 g twice daily [CYP3A4 inhibitor]	Voriconazole Cmax and AUCτ ↔	No dose adjustment required.
Azithromycin 500 mg once daily	Voriconazole Cmax and AUCτ ↔ Effect of voriconazole on erythromycin or azithromycin unknown.
Mycophenolic acid single dose 1 g [UDP-glucuronosyltransferase substrate]	Mycophenolic acid Cmax ↔ Mycophenolic acid AUCt ↔	No dose adjustment required.
Corticosteroids Prednisolone (single dose 60 mg) [CYP3A4 substrate]	Prednisolone Cmax ↑ 11 % Prednisolone AUC0-∞ ↑ 34 %	No dose adjustment required. Patients undergoing long-term treatment with voriconazole and corticosteroids (including inhaled, e.g. budesonide, and intranasal corticosteroids) should be closely monitored for adrenal dysfunction both during and after completion of voriconazole therapy (see section "Special instructions").
Ranitidine (150 mg twice daily) [increases gastric pH]	Voriconazole Cmax and AUCτ ↔	No dose adjustment required.

Special precautions for use.

Increased sensitivity.

Voriconazole should be prescribed with caution to patients with hypersensitivity to other azoles.

Cardiovascular disorders.

Voriconazole use has been 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 prior cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, or concomitant use of drugs that may contribute to this effect. Voriconazole should be used cautiously in patients with potentially proarrhythmic conditions, such as:

• congenital or acquired QTc interval prolongation;
• cardiomyopathy, particularly associated with heart failure;
• sinus bradycardia;
• existing symptomatic arrhythmia;
• concomitant use of medicinal products known to cause QTc prolongation.

Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be identified and corrected, if necessary, before and during treatment with voriconazole. A clinical study in healthy volunteers evaluated the effect of single doses of voriconazole up to four times the recommended daily dose on the QTc interval. No patient had a QTc interval exceeding the potentially clinically significant threshold of 500 ms.

Hepatotoxicity.

There are reports of rare cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis, and fulminant hepatic failure, some fatal). Cases of hepatic reactions occurred predominantly in patients with serious underlying conditions (mainly hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, have occurred in patients without other identifiable risk factors. Liver function abnormalities were usually reversible upon discontinuation of therapy.

Liver function monitoring.

Patients receiving voriconazole should be closely monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (specifically AST and ALT) at the start of voriconazole therapy and at least once weekly during the first month of treatment. The duration of treatment should be as short as possible; however, if continued based on benefit-risk assessment, the frequency of monitoring may be reduced to once monthly in the absence of changes in liver function tests.

If liver function test results increase significantly, voriconazole should be discontinued, except when medical evaluation of the benefit-risk ratio justifies continued use. Liver function monitoring should be performed in both children and adults.

Ocular adverse reactions.

There have been reports of prolonged adverse reactions affecting the eye, including blurred vision, optic neuritis, and optic disc edema.

Renal adverse reactions.

Acute renal failure has been observed in critically ill patients receiving voriconazole. Patients taking voriconazole may also be receiving nephrotoxic medicinal products and may have concomitant conditions that could lead to reduced renal function.

Renal function monitoring.

Patients should be monitored for the development of abnormal kidney function. This monitoring should include laboratory evaluation, particularly serum creatinine levels.

Pancreatic function monitoring.

Patients, particularly children, who have risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be closely monitored during voriconazole therapy. Monitoring of serum amylase or lipase may be considered in such clinical situations.

Serious skin adverse reactions.

• Photosensitivity.

The use of Voriconazole-Vista has been associated with photosensitivity reactions, including lichenoid reactions, lentigo, actinic keratosis, and pseudoporphyria. Patients, including children, should avoid direct sunlight exposure and take protective measures such as wearing protective clothing and using sunscreen with a high protection factor (SPF).

• Squamous cell carcinoma (SCC) of the skin has been observed in patients with a history of photosensitivity reactions. If photosensitivity reactions occur, consultation with specialists, including a dermatologist, is required. Consideration should be given to discontinuing voriconazole and using alternative antifungal agents. Dermatological evaluation should be performed systematically and regularly whenever voriconazole treatment continues despite the presence of photosensitivity-related lesions, to enable early detection and treatment of precancerous lesions. Voriconazole should be discontinued if precancerous lesions or squamous cell carcinoma are detected.
• Exfoliative skin reactions.

Exfoliative skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have occurred in patients receiving Voriconazole-Vista. Patients who develop a rash during treatment with Voriconazole-Vista should be closely monitored. The medicinal product should be discontinued if skin lesions progress.

Adrenal gland effects.

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

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

Patients undergoing long-term treatment with voriconazole and corticosteroids (including inhaled, e.g., budesonide, and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during and after voriconazole treatment (see section "Interaction with other medicinal products and other forms of interaction").

Long-term treatment.

Treatment or prophylaxis longer than 180 days (6 months) requires careful benefit-risk assessment; therefore, physicians should consider the possibility of reducing the dose of Voriconazole-Vista.

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

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed in transplant patients. If a patient develops bone pain and radiological findings suggest periostitis, discontinuation of voriconazole should be considered after consultation with other specialists.

Prophylaxis.

In cases of adverse events related to treatment (hepatotoxicity, severe skin reactions including photosensitivity and SCC, severe or prolonged ocular disorders, and periostitis), consideration should be given to discontinuing voriconazole and using alternative antifungal agents.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer).

Plasma phenytoin levels should be closely monitored when co-administered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk.

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate).

When voriconazole is co-administered with efavirenz, 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.

Glasdegib (CYP3A4 substrate).

Concomitant use of voriconazole is expected to increase plasma concentrations of glasdegib and increase the risk of QTc prolongation (see section "Special precautions for use"). 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 careful clinical monitoring are recommended (see section "Special precautions for use").

Rifabutin (potent CYP450 inducer).

When rifabutin is co-administered with voriconazole, careful monitoring of full blood count and rifabutin adverse reactions (such as uveitis) is recommended. Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk.

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate).

Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless benefit-risk assessment justifies the use of voriconazole.

Everolimus (CYP3A4 substrate, P-gp substrate).

Concomitant use of voriconazole and everolimus is not recommended, as voriconazole is expected to significantly increase everolimus concentrations. Currently, there are insufficient data to recommend a dose adjustment in this situation.

Naloxegol (CYP3A4 substrate).

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

Methadone (CYP3A4 substrate).

Frequent monitoring for methadone-related adverse reactions and toxicity, including QTc prolongation, is recommended when methadone is co-administered with voriconazole, as methadone levels increase with concomitant voriconazole use. Methadone dose reduction may be necessary.

Short-acting opioids (CYP3A4 substrates).

When co-administered with voriconazole, consider reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil). Since co-administration of alfentanil with voriconazole increases the half-life of alfentanil by four times, and published studies have shown that co-administration of voriconazole with fentanyl increases the mean AUC0-∞ of fentanyl, frequent monitoring for opioid-related adverse reactions (including prolonged respiratory monitoring) may be required.

Long-acting opioids (CYP3A4 substrates).

When co-administered with voriconazole, consider reducing the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone). Frequent monitoring for opioid-related adverse reactions may be required.

Fluconazole (CYP2C9, CYP2C19, and CYP3A4 inhibitor).

Concomitant oral administration of voriconazole and fluconazole resulted in a significant increase in Cmax and AUCτ of voriconazole in healthy volunteers. Dose reduction and/or frequency adjustment of voriconazole and fluconazole to counteract this effect has not been studied. Monitoring for voriconazole-related adverse reactions is recommended if voriconazole is administered after fluconazole.

Children. The safety and efficacy of Voriconazole-Vista in children under 2 years of age have not been established (see sections "Adverse reactions" and "Pharmacodynamics"). Voriconazole is recommended for use in children aged 2 years and older. Elevated liver enzyme levels occur more frequently in children (see section "Adverse reactions"). Liver function monitoring is required for both adults and children. In patients aged 2–12 years, oral bioavailability of the medicinal product may be limited due to malabsorption and very low body weight. Intravenous administration is recommended for these patients. Serious skin adverse reactions (including squamous cell carcinoma of the skin). The incidence of photosensitivity reactions is higher in children. If skin lesions progress toward squamous cell carcinoma in this patient group, enhanced sun protection measures should be implemented. Children exhibiting signs of photoaging, such as freckles or lentigo, should be referred to a dermatologist and advised to avoid sun exposure even after discontinuation of the medicinal product.

Important information about excipients.

One 50 mg film-coated tablet contains 7.5 mg of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

One 200 mg film-coated tablet contains 30 mg of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

One 50 mg film-coated tablet contains 64.94 mg of lactose monohydrate. One 200 mg film-coated tablet contains 259.76 mg of lactose monohydrate.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of voriconazole in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

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

Women of childbearing potential.

Women of childbearing potential must always use effective contraception during treatment.

Breastfeeding period.

Excretion of voriconazole into breast milk has not been studied. Breastfeeding should be discontinued when starting voriconazole treatment.

Reproductive function.

Animal studies did not demonstrate impaired fertility.

Ability to affect reaction speed when driving or operating machinery.

Voriconazole has a moderate effect on reaction speed when driving or operating machinery. It may cause transient and reversible visual disturbances, including blurred vision, altered/enhanced visual perception, and/or photophobia. Patients experiencing these symptoms should avoid potentially hazardous activities such as driving or operating machinery.

Dosage and Administration.

Route of administration.

Voriconazole-Vista should be taken at least 1 hour before or 1 hour after a meal. Monitoring of electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia is required before initiating treatment and throughout the course of therapy, with correction as necessary.

Treatment.

Adults.

Treatment should be initiated with a loading dose of Voriconazole-Vista to achieve on the first day a plasma concentration close to steady state. Due to the high bioavailability after oral administration (96%), a switch from intravenous to oral administration may be performed when clinically indicated.

Detailed dosage recommendations are provided in Table 7.

Table 7

Doses	Oral
	Patients with body weight ≥ 40 kg *	Patients with body weight ≤ 40 kg *
Loading dose (first 24 hours)	400 mg every 12 hours	200 mg every 12 hours
Maintenance dose (after first 24 hours)	200 mg twice daily	100 mg twice daily

*This also applies to patients aged 15 years and older.

Duration of treatment.

Treatment should be as short as possible, depending on the patient's clinical and mycological response. Administration of voriconazole for longer than 180 days (6 months) requires careful assessment of the benefit-risk ratio (see sections "Special precautions" and "Pharmacodynamics").

Dose adjustment (adults).

If the patient's response to treatment is inadequate, the maintenance dose may be increased to 300 mg orally twice daily. For patients with body weight less than 40 kg, the oral maintenance dose may be increased to 150 mg twice daily.

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

For use in prophylaxis, see information below.

Children (2 to 12 years) and adolescents with low body weight (12–14 years, body weight < 50 kg). The pediatric dose should be used, as voriconazole metabolism in adolescents is more similar to that in children than in adults.

Recommended dosing regimen

Doses	Orally
Loading dose (first 24 hours)	Not recommended
Maintenance dose (after first 24 hours)	9 mg/kg twice daily (maximum dose 350 mg twice daily)

Note: Recommended based on a population pharmacokinetic analysis that included 112 immunocompromised children aged 2 to 12 years and 26 immunocompromised adolescents aged 12 to 17 years.

Initiation of therapy should be with intravenous administration; oral therapy should only be considered after significant clinical improvement has occurred. It should be noted that voriconazole exposure after an 8 mg/kg intravenous dose will be twice as high compared to a 9 mg/kg oral dose. These recommendations for oral dosing in children are based on studies in which voriconazole was administered as a powder for oral suspension. The bioequivalence of the powder for oral suspension and tablets has not been studied in children. Due to the expected shorter gastrointestinal transit time in children, absorption of tablets in children may differ compared to adult patients. Therefore, for children aged 2 to 12 years, the oral suspension formulation is recommended.

Adolescents aged 12 to 14 years and weighing ≥ 50 kg; 15–17 years regardless of body weight.

Voriconazole dosage should be equivalent to the adult dosage.

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

If the patient's response to treatment is inadequate, the dose may be increased stepwise by 1 mg/kg (or stepwise by 50 mg if the initial dose was the maximum oral dose of 350 mg). If the patient cannot tolerate treatment, the dose should be reduced stepwise by 1 mg/kg (or stepwise by 50 mg if the initial dose was the maximum oral dose of 350 mg).

Use in children aged 2 to 12 years with hepatic or renal impairment has not been studied.

Prophylaxis in adults and children.

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

Dosing.

The recommended dosing regimen for prophylaxis is the same as for treatment in the corresponding 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 as prophylaxis for more than 180 days (6 months) requires careful assessment of the benefit-risk ratio.

The information below applies to both treatment and prophylaxis.

Dose adjustment.

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

If treatment-related adverse reactions occur, discontinuation of voriconazole and initiation of alternative antifungal agents should be considered (see section "Adverse reactions" and "Pharmacodynamics").

Dose adjustment when co-administered with other agents.

Phenytoin may be co-administered with voriconazole provided the maintenance dose of voriconazole is increased from 200 mg to 400 mg twice daily orally (from 100 mg to 200 mg twice daily orally in patients weighing less than 40 kg) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Combinations of voriconazole and rifabutin should be avoided if possible. However, if such combination is urgently needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg twice daily orally (from 100 mg to 200 mg twice daily orally in patients weighing less than 40 kg) (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.

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

Renal impairment does not affect the pharmacokinetic properties of voriconazole following oral administration. Dose adjustment is not necessary in patients with moderate to severe renal impairment (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 warrant dose adjustment.

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").

The use of Voriconazole-Vista in patients with severe chronic hepatic cirrhosis (Child-Pugh class C) has not been studied. Information on the safety of voriconazole in patients with liver test abnormalities (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and total bilirubin more than 5 times the upper limit of normal) is limited.

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

Children.

The safety and efficacy of voriconazole in children under 2 years of age have not been established. Voriconazole should be administered to children aged 2 years and older. Elevations in liver enzymes occur more frequently in children. Liver function should be monitored in both children and adults. Bioavailability after oral administration in children aged 2 to 12 years with malabsorption and very low body weight for age may be limited. In such cases, intravenous administration of voriconazole is recommended. The frequency of phototoxic reactions is higher in children. Since cases of squamous cell carcinoma (SCC) have been reported, strict sun protection measures are justified for this patient population. Children who exhibit signs of photoaging of the skin, such as lentigines or freckles, should avoid sun exposure and should undergo dermatological evaluation even after discontinuation of therapy.

Overdose .

Data are available for three cases of accidental overdose. All cases occurred in children who received an intravenous voriconazole dose up to five times higher than the recommended dose.

Symptoms. A single adverse reaction of photophobia lasting 10 minutes has been reported.

Treatment. There is no known antidote for voriconazole. Voriconazole is amenable to hemodialysis with a clearance of 121 mL/min. Hemodialysis may assist in removing voriconazole from the body in cases of overdose.

Adverse Reactions

The safety profile of voriconazole in adults is based on data from an integrated safety database encompassing more than 2000 individuals (including 1603 adult patients who participated in therapeutic studies) and an additional 270 adult patients from prophylaxis studies. This patient 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 were visual disturbances, pyrexia, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abnormal liver function tests, respiratory distress syndrome, and abdominal pain. The severity of adverse reactions was generally mild to moderate. No clinically significant differences were observed in analyses by age, race, or gender. Since most of the studies were open-label, all adverse reactions possibly related to voriconazole administration are listed below. Adverse reactions are based on pooled data from 1873 adult patients who participated in therapeutic (1603) and prophylaxis (270) studies.

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000); very rare (< 1/10,000); and not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System /organ class	very common	common	uncommon	rare	unknown
Infections and infestations		sinusitis	Pseudomembranous colitis
Benign, malignant and unspecified neoplasms (including cysts and polyps)					Squamous cell carcinoma*
Blood and lymphatic system disorders		agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anemia;	bone marrow failure, lymphadenopathy, eosinophilia	disseminated intravascular coagulation syndrome
Immune system disorders			hypersensitivity	anaphylactoid reactions
Endocrine disorders			adrenal insufficiency, hypothyroidism	hyperthyroidism
Metabolism and nutrition disorders	Peripheral edema1	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 disorders5, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia	hepatic encephalopathy, Guillain-Barré syndrome, nystagmus
Eye disorders	visual disturbance6	retinal hemorrhage	optic nerve disorders7, optic disc edema8, ocular hypertensive crisis, diplopia, scleritis, blepharitis	optic nerve atrophy, corneal clouding
Ear and labyrinth disorders			hearing loss, vertigo, tinnitus
Cardiac disorders		supraventricular arrhythmia, tachycardia, bradycardia, arterial hypotension, phlebitis	ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, QT interval prolongation on electrocardiogram, supraventricular tachycardia, thrombophlebitis, lymphangitis	polymorphic ventricular tachycardia (torsades de pointes), complete atrioventricular block, bundle branch block, junctional rhythm
Respiratory, thoracic and mediastinal disorders	dyspnea9	acute respiratory distress syndrome, pulmonary edema
Gastrointestinal disorders	abdominal pain, nausea, vomiting, diarrhea	dyspepsia, constipation, cheilitis, gingivitis	pancreatitis, duodenitis, glossitis, tongue swelling, peritonitis, gastroenteritis.
Hepatobiliary disorders	abnormal liver function tests	jaundice, cholestatic jaundice, hepatitis10	hepatic failure, hepatomegaly, cholecystitis, cholelithiasis
Skin and subcutaneous tissue disorders	rash	exfoliative dermatitis, maculopapular rash, pruritus, alopecia, erythema	Stevens-Johnson syndrome8, photosensitivity, purpura, urticaria, allergic dermatitis, papular rashes, macular rashes, eczema	toxic epidermal necrolysis8, drug reaction with eosinophilia and systemic symptoms (DRESS)8, angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug-induced toxicoderma	cutaneous lupus erythematosus*, melasma*, 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	pyrexia	chest pain, facial swelling11, chills, asthenia	influenza-like illness
Investigations		increased blood creatinine level	increased blood urea level, increased blood cholesterol level

*Adverse reactions identified after marketing authorization of the medicinal product

1 Including febrile neutropenia and neutropenia.

2 Including immune thrombocytopenic purpura.

3 Including nuchal muscle rigidity and tetany.

4 Including hypoxic-ischemic encephalopathy and metabolic encephalopathy.

5 Including akathisia and parkinsonism.

6 See section "Visual disturbances" in the "Adverse reactions" section.

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

8 See section "Special precautions for use".

9 Including dyspnea and exertional dyspnea.

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

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

Description of selected adverse reactions.

Visual disturbances. Visual disturbances during voriconazole administration are very common. In therapeutic studies, visual disturbances associated with voriconazole treatment were very common (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, visual disorders, presence of 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). In these studies, altered or enhanced visual perception, blurred vision, changes in color vision, or photophobia were observed in approximately 21% of patients during short- and long-term treatment. These visual disturbances were transient and fully reversible, with most resolving spontaneously within 60 minutes. No clinically significant long-term visual effects were observed. There is evidence of attenuation of these effects with repeated dosing of voriconazole. Visual disturbances were generally mild, rarely leading to discontinuation of the medicinal product and not associated with long-term complications. Visual disturbances may be related to higher plasma concentrations and/or doses. The mechanism of action is unknown, although the site of action is most likely the retina. In a study in healthy volunteers evaluating the effect of voriconazole on retinal function, voriconazole caused a reduction in wave amplitudes on electroretinography (ERG). ERG changes did not last longer than 29 days of treatment and were completely reversible after discontinuation of voriconazole. During post-marketing use of voriconazole, reports of prolonged visual adverse events have been recorded.

Cutaneous reactions. Cutaneous reactions were common in patients receiving voriconazole treatment; however, these patients had severe underlying conditions and were taking various concomitant medications. Most rashes were mild or moderate in severity. In rare cases, patients developed severe skin reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare), and erythema multiforme (rare), during treatment with Voriconazole-Vista. If a patient develops a rash, their condition should be closely monitored. Voriconazole should be discontinued if the skin reaction progresses. Reports of photosensitivity reactions such as freckling, lentigo, and actinic keratosis have been reported, particularly during prolonged therapy. Cases of cutaneous squamous cell carcinoma have been reported in patients receiving long-term voriconazole therapy; the mechanism of this phenomenon has not been established.

Liver function tests. During clinical trials, the overall incidence of elevations in transaminases >3 times the upper limit of normal (not necessarily considered an adverse reaction) was 18.0% in adults and 25.8% in children receiving voriconazole for treatment and prophylaxis. Abnormal liver function tests may be associated with high plasma concentrations and/or doses of the drug. Most abnormalities in liver function tests resolved during continued treatment without dose adjustment or after dose modification, including discontinuation of the drug. In patients with other severe underlying conditions, voriconazole use has been associated with cases of serious hepatotoxic reactions. Such reactions included jaundice, hepatitis, and fatal hepatic failure (see section "Special precautions for use").

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

Pediatric population. The safety of voriconazole was evaluated in children aged 2–12 years in pharmacokinetic studies and compassionate-use programs. The adverse reaction profile in children was similar to that in adults. However, a trend toward more frequent elevations in liver enzymes in children compared to adults was observed (incidence of elevated transaminases in children was 14.2% versus 5.3% in adults), reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the frequency of skin-related adverse reactions (particularly erythema) may be somewhat higher in children than in adults. The following adverse reactions, for which a causal relationship to voriconazole cannot be excluded, have been reported: photosensitivity reactions, arrhythmia, pancreatitis, increased blood bilirubin levels, elevated liver enzymes, rash, and optic disc edema. Pancreatitis has also been reported in children during post-marketing use of the medicinal product.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

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

Packaging. 10 film-coated tablets in a blister; 1 blister in a cardboard carton.

Prescription status. Prescription only.

Manufacturer: Sintón Hispania, S.L.

Manufacturer's address and location of operations.

C/ Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.

(Responsible for batch release)