Voritab®-50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORITAB® – 50 (VORITAB® – 50) VORITAB® – 200 (VORITAB® – 200)

Composition:

Active substance: voriconazole;

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

Excipients: lactose monohydrate, corn starch, colloidal anhydrous silicon dioxide, talc, magnesium stearate, potassium polacrilin, hypromellose, titanium dioxide (E 171), polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, white in color (for 50 mg); elongated, biconvex, film-coated tablets, white to slightly yellowish in color, with a break line on one side. Marbling may be observed (for 200 mg).

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-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. Across 10 therapeutic studies, the median average and maximum plasma concentrations for each individual patient 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 has not been established in therapeutic trials, and such a relationship has not been demonstrated in prophylaxis studies.

Pharmacokinetic/pharmacodynamic analysis of data from clinical trials identified a positive association between plasma concentrations of voriconazole and elevations in liver function tests as well as visual disturbances. Dose adjustment has not been established in prophylaxis studies.

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

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

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

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

In vitro activity of the drug has been demonstrated against various Curvularia 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 tests (serological, histopathological) should be obtained to isolate and identify the causative microorganisms. Therapy may be initiated before culture and laboratory results are available; however, once results are available, antimicrobial therapy should be adjusted accordingly.

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

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

Table 1.

EUCAST clinical breakpoints.

Species of Candida	MIC Breakpoint Values (mg/l)
	≤ S (Susceptible)	> R (Resistant)
Candida albicans1	0.06	0.25
Candida dubliniensis1	0.06	0.25
Candida glabrata	Insufficient data available
Candida krusei	Insufficient data available
Candida parapsilosis1	0.125	0.25
Candida tropicalis1	0.125	0.25
Candida guilliermondii2	Insufficient data available
Non-species related breakpoints for Candida3	Insufficient data available
Aspergillus fumigatus4	1	1
Aspergillus nidulans4	1	1
Aspergillus flavus	Insufficient data available5
Aspergillus niger	Insufficient data available5
Aspergillus terreus	Insufficient data available5
Non-species related breakpoints6	Insufficient data available5
1 Strains with MIC values above the susceptible/intermediate (S/I) breakpoint are rare or not yet reported. Testing for identification and antifungal susceptibility of any such isolate should be repeated, and if confirmed, the isolate should be sent to a reference laboratory. In the absence of evidence for clinical response to confirmed isolates with MICs above the current resistant breakpoint, they should be reported as resistant. Clinical response was achieved in 76% of infections caused by the species listed below when MICs were less than or equal to epidemiological cutoff values. 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 defined based on PK/PD data and do not depend on the MIC distribution of specific Candida species. They are intended only for organisms lacking specific breakpoints. 4 The technical uncertainty zone (ATU) is 2. Report as R with the comment: "In certain clinical situations (non-invasive forms of infection), voriconazole may be used if adequate exposure is ensured." 5 ECOFF values for these species are typically twice as high as for A. fumigatus. 6 Non-species-related breakpoints have not been defined.

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 advantages in patient survival compared to standard amphotericin B as first-line therapy for acute invasive aspergillosis were demonstrated in an open-label, randomized, multicenter study involving 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours for 7 days. The route of administration could 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 and radiographic/bronchoscopic findings 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, and clinically and statistically significant advantages of voriconazole were demonstrated both in terms of time to death and time to discontinuation due to drug toxicity. This study confirmed the results of a previous prospective study, which showed a positive treatment outcome 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 following bone marrow and solid organ transplantation, in patients with hematological malignancies, solid tumors, and AIDS.

Candidemia in non-neutropenic patients. The efficacy of voriconazole compared to a regimen of amphotericin B followed by fluconazole as first-line therapy for candidemia was demonstrated in an open-label comparative study. A total of 370 non-neutropenic patients (aged ≥12 years) with documented candidemia were enrolled, 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 was defined by the Data Monitoring Committee of the blinded study as resolution or improvement of all clinical signs and symptoms of infection, together with eradication of Candida from blood and infected deep tissue sites, assessed 12 weeks after completion of therapy. Patients not evaluable at 12 weeks post-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 evaluations by the Data Monitoring Committee at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after therapy completion), 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), in whom prior antifungal therapy, including fluconazole, had failed, were included in a clinical study. A favorable response to voriconazole treatment was observed in 24 patients (complete response in 15, partial response in 9). In patients infected with fluconazole-resistant non-Candida albicans strains, favorable outcomes with voriconazole treatment were observed in 3 out of 3 patients infected with C. krusei (complete response in all 3) 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 fungal pathogens has been demonstrated:

• Scedosporium species: a favorable response to voriconazole therapy was observed in 16 out of 28 patients infected with S. apiospermum (complete response in 6, partial response in 10) and in 2 out of 7 patients infected with S. prolificans (partial response in both). Additionally, a favorable response was observed in 1 out of 3 patients infected with more than one pathogenic organism, including various Scedosporium species;
• Fusarium species: successful therapy with voriconazole was achieved in 7 out of 17 patients (3 complete, 4 partial responses). Among these 7 patients, 3 had ocular infections, 1 had 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 above-mentioned rare fungal infections had prior intolerance or resistance to previously administered antifungal agents.

Primary prophylaxis of invasive fungal infections – efficacy in hematopoietic stem cell transplant recipients without prior confirmed or suspected invasive fungal infection. Voriconazole was compared with itraconazole as a primary prophylactic agent in an open-label, multicenter comparative study in adults and adolescents undergoing allogeneic hematopoietic stem cell transplantation, without prior confirmed or suspected invasive fungal infection. Success was defined as the ability to continue prophylaxis with the study drug for 100 days post-transplant (continuously for >14 days) and survival without prior confirmed or suspected invasive fungal infection within 180 days post-transplant. 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 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 efficacy endpoints are presented in the table below.

Criteria for efficacy	Voriconazole N=224	Itraconazole N=241	Difference in proportions and 95% confidence interval (CI)	P-value
Efficacy on day 180*	109 (48.7%)	80 (33.2%)	16.4% (7.7%, 25.1%)**	0.0002**
Efficacy on day 100	121 (54.0%)	96 (39.8%)	15.4% (6.6%, 24.2%)**	0.0006**
Duration of prophylaxis with investigational drug for at least 100 days	120 (53.6%)	94 (39.0%)	14.6% (5.6%, 23.5%)	0.0015
Survival rate up to day 180	184 (82.1%)	197 (81.7%)	0.4% (–6.6%, 7.4%)	0.9107
Development of 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 treatment with investigational drug	0	3 (1.2%)	1.2% (–2.6%, 0.2%)	0.0813

* Primary efficacy endpoint of the study.

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

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

Acute Myeloid Leukemia

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% CIs were obtained after adjustment for randomization.

Myeloablative conditioning regimen

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

* Primary efficacy endpoint of the study.

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

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

Secondary prophylaxis of invasive fungal infection – efficacy in recipients of allogeneic hematopoietic stem cell transplantation with prior proven 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 proven or suspected invasive fungal infection. The primary efficacy endpoint was the incidence of proven or suspected invasive fungal infections during the first year after hematopoietic stem cell transplantation. The ITT population included 40 patients with prior invasive fungal infections, including 31 with aspergillosis, 5 with candidiasis, and 4 with other types of invasive fungal infection. The mean duration of prophylaxis with the investigational drug in the ITT population was 95.5 days.

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

Duration of therapy. During clinical 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. One study included 31 patients with possible, proven, or probable invasive aspergillosis, of whom 14 had proven or probable invasive aspergillosis. These patients were included in the efficacy analysis of the modified intent-to-treat (mITT) population. In the second study, 22 patients with invasive candidiasis, including candidemia and esophageal candidiasis, requiring primary or salvage therapy were enrolled. Of these, 17 were included in the mITT efficacy analysis. In patients with invasive aspergillosis, the overall response rate at 6 weeks was 64.3% (9 out of 14); the response rate in patients aged 2 to 12 years was 40% (2 out of 5), and in patients aged 12 to 18 years was 77.8% (7 out of 9). In patients with candidemia, the overall response rate at the end of treatment was 85.7% (6 out of 7), and in patients with esophageal candidiasis 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.

QTc interval clinical studies. A placebo-controlled, randomized, crossover study with single-dose administration was conducted in healthy volunteers to evaluate the effect of investigational agents on the QTc interval. Three doses of voriconazole and ketoconazole were administered orally. The placebo-corrected mean maximum increase in QTc 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, specific population groups, and patients. After oral administration at doses of 200 mg or 300 mg twice daily for 14 days in patients at increased risk of aspergillosis (primarily patients with hematological malignancies), the pharmacokinetic parameters—rate and extent of absorption, accumulation, and non-linear pharmacokinetics—were similar to those observed in healthy volunteers.

Voriconazole pharmacokinetics are non-linear due to extensive metabolism. Increases in dose result in greater-than-proportional increases in exposure. It is estimated that increasing the oral dose from 200 mg to 300 mg twice daily increases exposure (AUCτ) by an average of 2.5-fold. An oral loading dose of 200 mg (or 100 mg for patients with body weight < 40 kg) achieves exposure equivalent to 3 mg/kg administered intravenously. An oral loading dose of 300 mg (or 150 mg for patients with body weight < 40 kg) achieves exposure equivalent to 4 mg/kg administered intravenously. After either oral or intravenous loading doses, plasma concentrations approaching steady-state are achieved within the first 24 hours of therapy. Without a loading dose regimen, steady-state plasma concentrations are generally reached by day 6 with repeated twice-daily dosing.

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) occurring 1–2 hours post-dose. Absolute oral bioavailability of voriconazole is 96%. When voriconazole is administered repeatedly with a high-fat meal, Cmax and AUCτ decrease by 34% and 24%, respectively. Gastric pH changes do not affect voriconazole absorption.

Distribution. The volume of distribution at steady state is estimated at 4.6 L/kg, indicating extensive tissue distribution. Plasma protein binding of voriconazole is approximately 58%. Voriconazole has been detected in measurable concentrations in cerebrospinal fluid samples from all 8 patients evaluated 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-subject pharmacokinetic variability.

In vivo studies indicate 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 African populations, the proportion of slow metabolizers is approximately 35%. Studies in healthy Caucasian and Japanese volunteers showed that exposure (AUCτ) in "slow metabolizers" is on average 4 times higher than in "extensive metabolizers" (homozygous fast metabolizers). Heterozygous "intermediate metabolizers" have on average 2-fold higher exposure than homozygous "extensive metabolizers."

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

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

After administration of radiolabeled voriconazole, approximately 80% of radioactivity was recovered in urine following multiple intravenous doses and 83% following multiple oral doses. The majority (> 94%) of radioactive substances were eliminated within the first 96 hours after both intravenous and oral administration.

The elimination half-life of voriconazole is dose-dependent and is approximately 6 hours after a 200 mg oral dose. Due to non-linear pharmacokinetics, half-life is not used to assess accumulation or elimination of voriconazole.

Pharmacokinetics in special patient populations.

Gender. In a multiple-dose oral study, Cmax and AUCτ 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 adjustments based on gender were not performed in the clinical program. Safety profiles and plasma concentrations of the drug in men and women were similar. Therefore, dose adjustment based on gender is not necessary.

Elderly patients. In a multiple-dose oral clinical study, 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 adjustments based on age were not performed in the clinical program. A relationship between plasma concentrations and age was observed. Safety profiles of voriconazole in younger and elderly patients were similar; therefore, dose adjustment in elderly patients is not required (see section "Dosage and administration").

Pediatric patients. 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 intravenous doses of 3, 4, 6, 7, and 8 mg/kg twice daily and multiple oral doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily (oral suspension powder) were evaluated in three pharmacokinetic studies in children. Loading doses of 6 mg/kg twice daily intravenously on day 1, followed by maintenance doses of 4 mg/kg twice daily intravenously and 300 mg twice daily orally (tablets), were evaluated in one pediatric pharmacokinetic study. This patient population showed higher inter-subject variability compared to adults.

Pharmacokinetic comparisons between children and adults showed that expected total exposure (AUCτ) in children after an intravenous loading dose of 9 mg/kg was comparable to that in adults after a 6 mg/kg intravenous loading dose. AUCτ in children after intravenous maintenance doses of 4 and 8 mg/kg twice daily was comparable to AUCτ in adults after 3 and 4 mg/kg twice daily intravenously. AUCτ in children after 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 8 mg/kg intravenous dose is approximately twice that after a 9 mg/kg oral dose.

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

Exposure in most older children was comparable to that in adults at equivalent dosing regimens. However, lower exposure was observed in some older children with low body weight compared to adults, suggesting a metabolic pattern more similar to younger children than adults. Based on population pharmacokinetic analysis, children aged 12–14 years with body weight < 50 kg should receive pediatric dosing (see section "Dosage and administration").

Renal impairment. In a study of single 200 mg doses administered to patients with normal renal function, mild renal impairment (creatinine clearance 41–60 mL/min), and severe renal impairment (creatinine clearance < 20 mL/min), the degree of renal impairment had minimal effect on voriconazole pharmacokinetics. Voriconazole plasma protein binding was similar across all renal function groups (see sections "Dosage and administration" and "Special warnings and precautions for use").

Hepatic impairment. After a single oral dose (200 mg) in patients with mild or 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 100 mg twice-daily maintenance dose 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 warnings and precautions for use").

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 used in adults and children for the treatment of:

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

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, and ivabradine, as increased plasma concentrations of these drugs may lead to QTc interval prolongation and, rarely, to development of torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with rifampicin, carbamazepine, and phenobarbital, as these drugs 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 doses of 400 mg per day or higher, as efavirenz at these doses significantly reduces voriconazole plasma concentrations in healthy volunteers. Voriconazole also significantly increases plasma concentrations of efavirenz (see section "Interaction with other medicinal products and other forms of interaction"; for use of lower efavirenz doses, see section "Special precautions").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily), as such doses of ritonavir lead to a significant reduction in voriconazole plasma concentrations in healthy volunteers (for use of lower ritonavir doses, see section "Special precautions").
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as increased plasma concentrations of these drugs may result in ergotism (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of voriconazole with naloxegol, a CYP3A4 substrate, as increased plasma concentrations of naloxegol may trigger opioid withdrawal symptoms (see section "Special precautions").
• Concomitant use of voriconazole with tolvaptan, as strong CYP3A4 inhibitors such as voriconazole significantly increase tolvaptan plasma concentrations (see section "Special precautions").
• Concomitant use of voriconazole with lurasidone, as substantial increase in lurasidone exposure may lead to serious adverse reactions (see section "Special precautions").
• Concomitant use with venetoclax at the initiation of treatment and during the dose titration phase of venetoclax, as voriconazole is likely to significantly increase venetoclax plasma concentrations and increase the risk of tumor lysis syndrome (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with St. John's wort (Hypericum perforatum) products (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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

Drug interaction studies were conducted in healthy male volunteers who received oral voriconazole 200 mg twice daily repeatedly until steady state was achieved. The results 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. Concomitant use is contraindicated in cases where voriconazole may also increase plasma concentrations of substances metabolized by CYP3A4 isoenzymes (e.g., certain antihistamines, quinidine, cisapride, pimozide, and ivabradine).

Information on interactions between voriconazole and other medicinal products is presented in Table 3. The direction of the arrow 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 defined time point;
AUC0–∞ – area under the concentration-time curve from time zero to infinity;
n/a – not applicable.

Interactions in the table are listed in the following order: concomitant use contraindicated, concomitant use requires dose adjustment and careful clinical and biological monitoring, concomitant use has no significant pharmacokinetic interactions but may have clinical relevance in the therapeutic area.

Table 3.

Medicinal product (mechanism of interaction)	Interaction Mean geometric change, %	Recommendations for concomitant use
Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine (CYP3A4 substrates)	Although appropriate studies have not been conducted, increased plasma concentrations of these agents may lead to QTc prolongation and rarely to development of ventricular tachycardia of the "torsade de pointes" type.	Contraindicated (see section "Contraindications").
Carbamazepine and long-acting barbiturates, e.g. phenobarbital, mephobarbital (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; inhibitor and substrate of CYP3A4) 400 mg once daily with voriconazole 200 mg twice daily* Efavirenz 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 is used concomitantly with efavirenz, 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 considerations")
Ergot alkaloids, including but not limited to: ergotamine and dihydroergotamine (CYP3A4 substrates)	Although appropriate studies have not been conducted, voriconazole may increase plasma concentrations of ergot alkaloids and lead to development of ergotism.	Contraindicated (see section "Contraindications").
Lurasidone (CYP3A4 substrate)	Although voriconazole has not been studied, it may significantly increase lurasidone plasma concentrations.	Contraindicated (see section "Contraindications").
Naloxegol (CYP3A4 substrate)	Although voriconazole has not been studied, it is likely to significantly increase naloxegol plasma concentrations.	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 the benefit outweighs the 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 is used concomitantly with voriconazole, careful monitoring of blood counts and rifabutin-related adverse reactions (such as 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; inhibitor and substrate of CYP3A4) 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 the benefit outweighs the 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 (CYP3A substrate)	Although voriconazole has not been studied, it may significantly increase tolvaptan plasma concentrations.	Contraindicated (see section "Contraindications").
Venetoclax (CYP3A substrate)	Although studies have not been conducted, voriconazole is likely to significantly increase venetoclax plasma concentrations.	Concomitant use of voriconazole is contraindicated at the beginning of venetoclax treatment and during the dose titration phase (see section "Contraindications"). Dose reduction of venetoclax should be considered as indicated in the venetoclax product information during stable daily dosing; careful monitoring for signs of toxicity is recommended.
Fluconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4), 200 mg once daily	Cmax of voriconazole ↑ 57 % AUCτ of voriconazole ↑ 79 % Cmax of fluconazole – not determined AUCτ of fluconazole – not determined	It is not established what dose reduction and/or frequency adjustment of voriconazole and fluconazole is necessary to avoid this effect. When voriconazole is administered immediately after fluconazole, monitoring for adverse reactions associated with voriconazole 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 the benefit outweighs the risk. When phenytoin is used concomitantly with voriconazole, careful monitoring of plasma phenytoin 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 (inducer of CYP2C9 and CYP2C19)	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 (CYP3A4 substrate)	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 considerations").
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 is recommended (see section "Special considerations").
Anticoagulants Warfarin (CYP2C9 substrate) (single 30 mg warfarin dose concomitantly with 300 mg voriconazole twice daily) Other oral coumarins, such as phenprocoumon, acenocoumarol (CYP2C9 and CYP3A4 substrates)	Prothrombin time increased approximately twofold. Although appropriate studies have not been conducted, voriconazole may increase plasma concentrations of coumarins and thus prolong prothrombin time.	Close monitoring of prothrombin time and other appropriate coagulation parameters is recommended, with appropriate adjustment of anticoagulant doses.
Ivacaftor (CYP3A4 substrate)	Although studies have not been conducted, voriconazole is likely to increase ivacaftor plasma concentrations, increasing the risk of adverse effects.	Dose reduction of ivacaftor is recommended.
Benzodiazepines Midazolam (0.05 mg/kg intravenous single dose) Midazolam (7.5 mg oral single dose) Other benzodiazepines (e.g., triazolam, alprazolam) (CYP3A4 substrates)	In an independent published study, AUC of midazolam 0-∞ ↑ 3.7-fold. In an independent published study, Cmax of midazolam ↑ 3.8-fold AUC of midazolam 0-∞ ↑ 10.3-fold. Although voriconazole has not been studied, it may increase plasma concentrations of other benzodiazepines metabolized by CYP3A4 and cause prolonged sedative effects.	Dose reduction of benzodiazepines should be considered.
Immunosuppressants (CYP3A4 substrates) Sirolimus (single 2 mg dose) Everolimus Cyclosporine (in stable renal transplant recipients on continuous cyclosporine therapy) Tacrolimus (single 0.1 mg/kg dose)	In an independent published study: Cmax of sirolimus ↑ 6.6-fold, AUC0-∞ of sirolimus ↑ 11-fold. Although voriconazole has not been studied, it may significantly increase everolimus plasma concentrations. Cmax of cyclosporine ↑ 13 % AUCτ of cyclosporine ↑ 70 % Cmax of tacrolimus ↑ 117 % AUCt of tacrolimus ↑ 221 %	Concomitant use is contraindicated (see section "Contraindications"). Concomitant use of voriconazole and everolimus is not recommended, as voriconazole is expected to significantly increase everolimus concentrations (see section "Special considerations"). 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 the dose increased if necessary. At initiation of voriconazole therapy in patients already receiving tacrolimus, a reduction of tacrolimus dose to one-third of the original dose and close monitoring of tacrolimus levels are recommended. Elevated tacrolimus levels are associated with nephrotoxic effects. After discontinuation of voriconazole, tacrolimus levels should be closely monitored and the 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 long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone) should be considered. Frequent monitoring for opioid-related adverse reactions is recommended.
Methadone (CYP3A4 substrate) (32-100 mg once daily)	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 increased 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 adjustment may be necessary.
Omeprazole (inhibitor of CYP2C19; substrate of CYP2C19 and CYP3A4) 40 mg once daily*	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.	Dose adjustment of voriconazole is not 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 %	Frequent 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 short-acting opioids metabolized by CYP3A4 (e.g., sufentanil) should be considered. 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 statins metabolized by CYP3A4 cannot be avoided, dose reduction of the statin should be considered.
Sulfonylurea derivatives, including but not limited to: tolbutamide, glipizide, glyburide (CYP2C9 substrates)	Although appropriate studies have not been conducted, voriconazole may increase plasma levels of sulfonylurea derivatives and thus cause hypoglycemia.	Close monitoring of blood glucose levels is required. Dose reduction of sulfonylurea derivatives should be considered.
Vinca alkaloids, including but not limited to: vincristine and vinblastine (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole may increase plasma levels of vinca alkaloids and lead to neurotoxic effects.	Dose reduction of vinca alkaloids should be considered.
Other HIV protease inhibitors, including but not limited to: saquinavir, amprenavir and nelfinavir* (CYP3A4 inhibitors)	Clinical studies have not been conducted. In vitro studies indicate that voriconazole may inhibit the metabolism of HIV protease inhibitors and that voriconazole metabolism 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, along with consideration of dose adjustment.
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 that voriconazole may inhibit NNRTI metabolism. Based on the effect of efavirenz 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, along with consideration of dose adjustment.
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 (non-specific CYP450 inhibitor and increases gastric juice pH) (400 mg twice daily)	Cmax of voriconazole ↑ 18 % AUCτ of voriconazole ↑ 23 %	No dose adjustment required.
Digoxin (P-glycoprotein substrate) (0.25 mg once daily)	Cmax of digoxin ↔ AUCτ of digoxin ↔	No dose adjustment required.
Indinavir (inhibitor and substrate of CYP3A4) (800 mg three times daily)	Cmax of voriconazole ↔ AUCτ of voriconazole ↔ Cmax of indinavir ↔ AUCτ of indinavir ↔	No dose adjustment required.
Macrolide antibiotics Erythromycin (CYP3A4 inhibitor) (1 g twice daily) 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.
Myfophenolic acid (substrate of UDP-glucuronosyltransferase) (1 g single dose)	Cmax and AUCt of mycophenolic acid ↔	No dose adjustment required.
Corticosteroids Prednisolone (CYP3A4 substrate) (60 mg single dose)	Cmax of prednisolone ↑ 11 % AUC0-∞ of prednisolone ↑ 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 voriconazole treatment (see section "Special considerations").
Ranitidine (increases gastric juice pH) (150 mg twice daily)	Cmax and AUCτ of voriconazole ↔	No dose adjustment required.
Flucloxacillin (CYP450 inducer)	Significant reduction in voriconazole plasma concentrations has been reported.	If concomitant use of voriconazole with flucloxacillin cannot be avoided, monitoring for potential loss of voriconazole efficacy (e.g., via therapeutic drug monitoring) is recommended; voriconazole dose increase may be necessary.

Special precautions for use.

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

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

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

Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and corrected if necessary before initiating voriconazole therapy and during treatment (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 participant did the duration of this interval exceed the potentially clinically significant threshold of 500 ms (see section "Pharmacodynamics").

Hepatotoxicity. During clinical trials, serious hepatic reactions (including clinically evident hepatitis, cholestasis, and fulminant hepatic failure, including fatal cases) have been observed with voriconazole use. Hepatic reactions were primarily observed in patients with severe underlying conditions (especially 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 normalized after discontinuation of therapy (see section "Adverse reactions").

Liver function monitoring. Patients receiving voriconazole should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (particularly 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 risk-benefit assessment (see section "Dosage and administration"), the frequency of monitoring may be reduced to once monthly provided there are no changes in liver test results.

If liver test results show significant elevation, voriconazole should be discontinued, except in cases where clinical risk-benefit assessment justifies continued use.

Liver function monitoring is required in both children and adults.

Serious cutaneous adverse reactions.

• Photosensitivity. The use of voriconazole has additionally been 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, etc.). All patients, including children, should avoid direct sunlight exposure, wear protective clothing, and use sunscreen with a high protection factor (SPF) during voriconazole therapy.
• Squamous cell carcinoma of the skin. Among patients who developed squamous cell carcinoma of the skin or Bowen’s disease, some had prior history of photosensitivity reactions. In case of photosensitivity reactions, multidisciplinary physician consultations should be conducted, voriconazole should be discontinued, and alternative antifungal agents should be considered, with referral to a dermatologist. If voriconazole treatment continues, a dermatologist should systematically and regularly examine the patient for early detection and treatment of possible precancerous lesions. If precancerous skin lesions, squamous cell carcinoma, or Bowen’s disease are detected, voriconazole therapy should be discontinued (see section "Long-term therapy" below).
• Exfoliative skin reactions.
• Serious skin adverse reactions (SCAR), such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported and may be life-threatening or fatal during voriconazole use. Skin rashes should be carefully monitored, and if lesions progress, the drug should be discontinued.

Adrenal gland effects

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, including voriconazole, both with and 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-associated inhibition of CYP3A4 metabolism may lead to corticosteroid excess and adrenal suppression (see section "Special precautions for use"). Cushing’s syndrome, with or without subsequent adrenal insufficiency, has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients receiving long-term voriconazole and corticosteroid therapy (including inhaled corticosteroids such as budesonide and intranasal corticosteroids) should be closely monitored for adrenal cortex dysfunction both during and after discontinuation of voriconazole (see section "Special precautions for use"). Patients should be instructed to seek immediate medical attention if signs and symptoms 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. Additionally, physicians should consider reducing the voriconazole dose (see sections "Dosage and administration" and "Pharmacodynamics").

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

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

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

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

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

Pancreatic function monitoring. Careful monitoring of patients, especially children, with risk factors for acute pancreatitis such as recent chemotherapy or hematopoietic stem cell transplantation, is recommended during drug use. 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. Increased liver enzyme levels occur more frequently in children (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 such patients.

• Serious cutaneous 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 protective measures against sunlight exposure should be implemented. Children showing signs of photoaging, such as freckles or lentigo, should be under dermatological surveillance and should avoid sun exposure even after discontinuation of the drug.

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

Phenytoin (CYP2C9 substrate and potent CYP450 inducer). Careful monitoring of plasma phenytoin levels is recommended when voriconazole and phenytoin 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 expected to increase glasdegib plasma concentrations 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 close clinical monitoring are recommended (see section "Special precautions for use").

Rifabutin (potent CYP450 inducer). Careful monitoring of complete blood count and rifabutin-related adverse reactions (such as uveitis) is required when voriconazole and rifabutin are used concomitantly. Concomitant use of voriconazole and rifabutin should be avoided unless 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 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 dosing regimens (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 voriconazole coadministration. Dose reduction of methadone may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Short-acting opioids (CYP3A4 substrates). When short-acting opioids and voriconazole are used concomitantly, consider reducing the dose of alfentanil, fentanyl, and other structurally similar short-acting opioids metabolized by CYP3A4 (e.g., sufentanil) (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of opioid-related adverse reactions (including prolonged respiratory function monitoring) may be necessary, as the elimination half-life of alfentanil is prolonged 4-fold with concomitant use of voriconazole, and published data from one study indicate that concomitant use of fentanyl and voriconazole increases the mean AUC0–∞ of fentanyl.

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

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

The 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.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of voriconazole in pregnant women. Animal studies have demonstrated reproductive toxicity. The potential risk to humans is unknown.

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

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

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Voriconazole should be administered at least 1 hour before or after a meal.

Electrolyte imbalances such as hypokalaemia, hypomagnesaemia, and hypocalcaemia should be monitored before initiating voriconazole treatment and during therapy, and corrected if necessary (see section "Special Warnings and Precautions for Use").

Treatment.

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

Detailed dosage recommendations are provided in Table 4.

Table 4.

Dosing regimen	For oral administration
	Patients weighing 40 kg or more*	Patients weighing less than 40 kg*
Loading doses (during the first 24 hours of treatment)	400 mg every 12 hours	200 mg every 12 hours
Maintenance doses (after 24 hours from the start of treatment)	200 mg twice daily	100 mg twice daily

• Including patients aged 15 years and older.

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

Dose adjustment for adults. If the patient does not show an adequate response to treatment, the maintenance dose may be increased to 300 mg orally twice daily. For patients with body weight less than 40 kg, the dose may be increased to 150 mg orally twice daily.

For patients who do not 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).

Information on the use of the drug for prophylaxis is provided below.

Prophylaxis in adults and children.

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

Dosing. The recommended dosing regimen for prophylaxis is the same as for treatment in the corresponding age groups (see Tables 4 and 5).

Duration of prophylaxis. The safety and efficacy of voriconazole use for more than 180 days have not been adequately studied in clinical trials.

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

The following information applies to both treatment and prophylaxis.

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

If treatment-related adverse reactions occur, consideration should be given to discontinuing voriconazole and initiating alternative antifungal agents (see sections "Adverse reactions" and "Pharmacodynamics").

Dose adjustment when used concomitantly with other agents. Phenytoin may be used concomitantly with voriconazole provided the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally twice daily (from 100 mg to 200 mg orally twice daily for patients with body weight less than 40 kg) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Combinations of voriconazole and rifabutin should be avoided whenever possible. However, if such combination is urgently needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally twice daily (from 100 mg to 200 mg orally twice daily for patients with body weight less than 40 kg) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

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

Elderly patients. No dose adjustment is necessary for elderly patients (see section "Pharmacokinetics").

Renal impairment. Renal impairment does not affect the pharmacokinetic properties of voriconazole when administered orally. No dose adjustment is necessary for 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 necessitate dose adjustment.

Hepatic impairment. For patients with mild to moderate hepatic cirrhosis (Child–Pugh class A or B), standard loading dose regimens are recommended, while the maintenance dose should be halved (see section "Pharmacokinetics").

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

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

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

Children.

The drug is indicated for use in children aged 2 years and older. Safety and efficacy of the drug in children under 2 years of age have not been established.

For children aged 2–12 years and children aged 12–14 years with body weight < 50 kg, the following treatment regimen is recommended:

Table 5.

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

It is recommended to initiate therapy with intravenous administration, and the possibility of switching to oral administration should only be considered after significant clinical improvement has been achieved. It should be noted that an intravenous dose of 8 mg/kg provides voriconazole exposure approximately twice that achieved with an oral dose of 9 mg/kg.

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

Dose adjustment for pediatric patients aged 2–12 years and for patients aged 12–14 years with body weight <50 kg. If the patient's response to treatment is inadequate, the dose may be increased by 1 mg/kg (or by 50 mg if the maximum oral dose of 350 mg was initially used). If the patient does not tolerate the treatment, the dose should be reduced by 1 mg/kg (or by 50 mg if the initial maximum oral dose of 350 mg was used).

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

Overdose.

During clinical trials, three cases of accidental overdose were reported. All three cases occurred in children who received intravenous doses up to five times higher than the recommended dose. The only adverse reaction reported was photophobia lasting 10 minutes. There is no known antidote for voriconazole.

The clearance of voriconazole during hemodialysis is 121 ml/min. Hemodialysis may assist in the removal of 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 group is sufficiently diverse and includes patients with hematological malignancies, HIV-infected patients with esophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidemia or aspergillosis, and healthy volunteers.

The most commonly reported adverse reactions included visual disturbances, pyrexia, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abnormal liver function tests, respiratory disorders, and abdominal pain.

Overall, adverse reactions were mild to moderate in severity. Analysis of safety data showed no clinically significant differences according to age, race, or gender.

Since most of the studies were open-label, all adverse reactions listed below are potentially causally related to the use of the medicinal product. Adverse reactions are defined based on combined data from 1873 adult patients who participated in therapeutic (1603) and prophylaxis (270) studies. Adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.

Infections and infestations.

Common: Sinusitis.

Uncommon: Pseudomembranous colitis.

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

Common: Squamous cell carcinoma* or Bowen’s disease.

Blood and lymphatic system disorders.

Common: Agranulocytosis¹, pancytopenia, thrombocytopenia², leukopenia, anemia.

Uncommon: Bone marrow failure, lymphadenopathy, eosinophilia.

Rare: Disseminated intravascular coagulation syndrome.

Immune system disorders.

Uncommon: Hypersensitivity.

Rare: Anaphylactoid reactions.

Endocrine disorders.

Uncommon: Adrenal insufficiency, hypothyroidism.

Rare: Hyperthyroidism.

Metabolism and nutrition disorders.

Very common: Peripheral edema.

Common: Hypoglycemia, hypokalemia, hyponatremia.

Psychiatric disorders.

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

Nervous system disorders.

Very common: Headache.

Common: Seizures, syncope, tremor, hypertension³, paraesthesia, somnolence, dizziness.

Uncommon: Brain edema, encephalopathy⁴, extrapyramidal disorders⁵, peripheral neuropathy, ataxia, hypoaesthesia, dysgeusia.

Rare: Hepatic encephalopathy, Guillain–Barré syndrome, nystagmus.

Eye disorders.

Very common: Visual disturbances⁶.

Common: Retinal hemorrhage.

Uncommon: Optic nerve disorders⁷, optic disc edema⁸, ocular hypertensive crisis, diplopia, scleritis, blepharitis.

Rare: Optic nerve atrophy, corneal opacity.

Ear and labyrinth disorders.

Uncommon: Hearing loss, vertigo, tinnitus.

Cardiac disorders.

Common: Supraventricular arrhythmia, tachycardia, bradycardia.

Uncommon: Ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, QT interval prolongation on electrocardiogram, supraventricular tachycardia.

Rare: Torsades de pointes, complete atrioventricular block, bundle branch block, nodal rhythm.

Vascular disorders.

Common: Arterial hypotension, phlebitis.

Uncommon: Thrombophlebitis, lymphangitis.

Respiratory, thoracic and mediastinal disorders.

Very common: Dyspnea⁹.

Common: Acute respiratory distress syndrome, pulmonary edema.

Gastrointestinal disorders.

Very common: Diarrhea, vomiting, abdominal pain, nausea.

Common: Cheilitis, dyspepsia, constipation, gingivitis.

Uncommon: Peritonitis, pancreatitis, tongue swelling, duodenitis, gastroenteritis, glossitis.

Hepatobiliary disorders.

Very common: Abnormal liver function tests.

Common: Jaundice, cholestatic jaundice, hepatitis¹⁰.

Uncommon: Hepatic failure, hepatomegaly, cholecystitis, cholelithiasis.

Skin and subcutaneous tissue disorders.

Very common: Rash.

Common: Exfoliative dermatitis, alopecia, maculopapular rash, pruritus, photosensitivity, erythema.

Uncommon: Stevens–Johnson syndrome (SJS), purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema.

Rare: Toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, toxidermia.

Not known: Cutaneous lupus erythematosus*, freckles*, lentigo*.

Musculoskeletal and connective tissue disorders.

Common: Back pain.

Uncommon: Arthritis, periostitis*.

Renal and urinary disorders.

Common: Acute renal failure, hematuria.

Uncommon: Renal tubular necrosis, proteinuria, nephritis.

General disorders and administration site conditions.

Very common: Pyrexia.

Common: Chest pain, facial edema¹¹, asthenia, chills.

Uncommon: Administration site reaction, influenza-like illness.

Investigations.

Common: Increased blood creatinine level.

Uncommon: Increased blood urea level, increased blood cholesterol level.

* Adverse reactions identified after marketing authorization.

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 disturbances" under "Adverse Reactions".

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

⁸ See section "Special precautions for use".

⁹ Including dyspnea and exertional dyspnea.

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

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

Visual disturbances. Visual disturbances (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorders, rainbow-colored halos in the visual field, night blindness, oscillopsia, photopsia, flickering scotoma, reduced visual acuity, visual brightness, visual field defect, floaters in the vitreous body, and xanthopsia) were very commonly observed during clinical and therapeutic studies and were associated with voriconazole use. These visual disturbances were reversible and spontaneously resolved within 60 minutes in most cases; no clinically significant long-term visual effects were observed. Symptoms tended to diminish with repeated dosing. Visual disturbances were generally mild, rarely led to discontinuation of the drug, and were not associated with long-term sequelae. Visual disturbances may be related to high plasma concentrations and/or drug doses. The mechanism of visual disturbances is unknown, although the drug likely affects the retina. Voriconazole administration resulted in reduced amplitude of waves on electroretinogram during a clinical study assessing the effect of voriconazole on retinal function in healthy volunteers. Changes on electroretinogram did not progress over 29 days of therapy and fully resolved after discontinuation of voriconazole.

Post-marketing reports have described prolonged ocular adverse reactions; see section "Special precautions for use".

Skin reactions. Skin reactions were very commonly observed in patients receiving voriconazole during clinical trials; however, these patients were concurrently receiving multiple other medications for treatment of severe underlying conditions. Most rashes were mild or moderate in severity. However, serious skin adverse reactions (SCAR), such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during use of voriconazole and may be life-threatening or fatal. Skin reactions should be closely monitored, and if lesions progress, the drug should be discontinued.

If a rash develops, the patient should be carefully monitored, and voriconazole should be discontinued if lesions progress.

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

Cases of squamous cell carcinoma have been reported in patients receiving long-term voriconazole; the mechanism is not established (see section "Special precautions for use").

Liver function tests. During clinical trials, the overall incidence of transaminase elevations >3 times the upper limit of normal (not necessarily considered an adverse reaction) was 18.0% (319/1768) in adults and 25.8% (73/283) in children receiving voriconazole for treatment or prophylaxis. Abnormal liver function tests may be associated with high plasma concentrations and/or drug doses. Most abnormalities resolved during continued treatment without dose adjustment or after dose adjustment, including discontinuation of the drug.

In patients with other severe underlying conditions, voriconazole use has been associated with serious hepatotoxic reactions, including jaundice, hepatitis, and fatal hepatic failure (see section "Special 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, treatment discontinuation due to adverse reactions occurred in 39.3% of patients receiving voriconazole compared to 39.6% in the itraconazole group.

Treatment-related hepatic adverse reactions led to permanent discontinuation of the investigational drug 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 12–18 years (119), who received voriconazole for prophylaxis (183) and treatment (105) in clinical trials. Safety was also assessed 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, a trend toward higher incidence of elevated liver enzymes in children compared to adults was observed (transaminase elevation occurred in 14.2% of children versus 5.3% of adults), reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the frequency of skin-related adverse reactions (particularly erythema) may be somewhat higher in children than in adults. In 22 patients under 2 years of age treated with voriconazole within compassionate use programs, the following adverse reactions, which cannot be excluded as being related to voriconazole, were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), increased blood bilirubin (1), increased liver enzymes (1), rash (1), and optic disc edema (1). Pancreatitis has also been reported in children during post-marketing use of the drug.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Photosensitivity reactions have been reported, particularly during prolonged treatment.

Cases of squamous cell carcinoma have been reported in patients receiving long-term voriconazole; the mechanism is not established (see section "Special precautions for use").

Children. Post-marketing experience suggests that the frequency of skin-related adverse reactions (particularly erythema) may be somewhat higher in children than in adults.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It enables monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, out of reach of children.

Packaging.

10 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.