Voriconazole zentiva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VORICONAZOLE ZENTIVA (VORICONAZOLE ZENTIVA)

Composition:

Active substance: voriconazole;

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

Excipients: lactose monohydrate; pregelatinized corn starch; sodium croscarmellose; povidone K30; colloidal anhydrous silicon dioxide; magnesium stearate;

film coating: Opadry II White OY-LS-28908, containing: titanium dioxide (E 171); lactose monohydrate; hypromellose 15 cP; hypromellose 3 cP; hypromellose 50 cP; polyethylene glycol 4000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: white to off-white, round biconvex film-coated tablets with the code V50 on one side;

200 mg tablets: white to off-white, oval biconvex film-coated tablets with the code V200 on one side.

Pharmacotherapeutic group.

Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C03.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics/Pharmacodynamics. In clinical studies, the median average and maximum plasma concentrations in individual patients were 2425 ng/mL (interquartile range 1193–4380 ng/mL) and 3742 ng/mL (interquartile range 2027–6302 ng/mL), respectively. A positive relationship between average, maximum, or trough plasma concentrations of voriconazole and efficacy has not been established in therapeutic trials, nor has such a relationship been demonstrated in prophylaxis studies.

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

Clinical efficacy and safety. Voriconazole has demonstrated in vitro antifungal activity against a broad range of Candida species (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all tested Aspergillus species. In addition, voriconazole has shown in vitro fungicidal activity against emerging fungal pathogens such as Scedosporium and 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, 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 for which voriconazole has shown efficacy (often with partial or complete response) include isolated infections caused by various Alternaria species, Blastomyces dermatitidis, Blastoschizomyces capitatus, various Cladosporium species, Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, various Penicillium species (including P. marneffei), Phialophora richardsiae, Scopulariopsis brevicaulis, and various Trichosporon species, including infections caused by T. beigelii.

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

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

Clinical breakpoints. Prior to initiating therapy, fungal cultures and other appropriate laboratory tests (serological, histopathological) should be obtained to isolate and identify causative pathogens. Therapy may be initiated before culture and laboratory results are available; however, once results are obtained, etiologic therapy should be adjusted accordingly.

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

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

Table 1

EUCAST susceptibility breakpoints

Species 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. Any such strains should be re-identified and their antifungal susceptibility retested; if the result is confirmed, the isolate should be referred to a reference laboratory. The strain should be considered resistant until clinical evidence demonstrates response to isolates with MICs above the current resistance breakpoint. For infections caused by the species listed above, a 76% clinical response rate was achieved when MICs were at or below the 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 established based on PK/PD data and do not depend on the MIC distribution of a specific Candida species. They should only be used for microorganisms lacking their own established 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 still 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.

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

Infections caused by Aspergillus: efficacy in aspergillosis in patients with poor prognosis. Voriconazole demonstrates in vitro fungicidal activity against various species of Aspergillus. The efficacy of voriconazole and its advantages in terms of patient survival compared to the standard comparator drug amphotericin B as first-line therapy for acute invasive aspergillosis were demonstrated in an open-label, randomized, multicenter study involving immunocompromised patients treated over 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 (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 drug, 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 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 after bone marrow and solid organ transplantation, in patients with hematologic malignancies, malignant tumors, and AIDS.

Candidemia in non-neutropenic patients. The efficacy of voriconazole compared to a treatment regimen of amphotericin B followed by fluconazole as first-line therapy for candidemia was demonstrated in an open comparative study. Non-neutropenic patients (aged 12 years and older) with documented candidemia were enrolled. 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 Study Data Review Committee, was defined as the disappearance/reduction of all clinical signs of infection together with eradication of Candida from blood and infected deep tissue sites 12 weeks after completion of therapy. Outcomes for patients not evaluated at 12 weeks after completion of therapy were considered unfavorable. According to this analysis, a favorable treatment outcome was observed in 41% of patients in both treatment groups.

In a secondary analysis using assessments by the Study Data Review Committee at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after completion of therapy), the rates of favorable response to voriconazole and to amphotericin B followed by fluconazole were 65% and 71%, respectively. The rates of favorable treatment outcome as assessed by investigators at each of these evaluable time points are presented in Table 2.

Table 2

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

Infections caused by various Scedosporium and Fusarium species. The efficacy of voriconazole against rare pathogenic fungi such as Scedosporium species and Fusarium species has been demonstrated.

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

Primary prophylaxis of invasive fungal infections – efficacy in hematopoietic stem cell transplant recipients without previously confirmed or suspected invasive fungal infection. Voriconazole was compared with itraconazole as a primary prophylactic agent in an open-label, multicenter comparative study in adults and adolescents undergoing allogeneic hematopoietic stem cell transplantation, without previously confirmed or suspected invasive fungal infection. Success was defined as the ability to continue prophylaxis with the study drug for 100 days post-transplantation (continuously for >14 days) and survival without confirmed or suspected invasive fungal infection within 180 days after hematopoietic stem cell 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 hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 patients received itraconazole. The mean duration of prophylaxis with the study drug 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

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 the study 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 the period of study drug administration	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.

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 Table 4.

Table 4

Acute Myeloid Leukemia

Criteria for effectiveness	Voriconazole (N=98)	Itraconazole (N=109)	Difference in proportions 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 by 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 obtained after adjustment for randomization.

Table 5

Myeloablative conditioning regimen.

Criteria for effectiveness	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%) **
Effectiveness 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% CI were obtained after adjustment for randomization.

Secondary prophylaxis of invasive fungal infection – efficacy in hematopoietic stem cell transplant recipients with prior proven or suspected invasive fungal infection. Voriconazole was studied as a secondary prophylactic agent in an open-label, non-comparative, multicenter trial 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 infections. The mean duration of prophylactic treatment with the study drug in the ITT population was 95.5 days.

Proven or suspected invasive fungal infections occurred in 7.5% (3/40) of patients during the first year after hematopoietic stem cell transplantation, including one case of candidemia, one case of 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 the studies, 705 patients received voriconazole for longer than 12 weeks, and 164 patients for longer than 6 months.

Pediatric population. 61 pediatric patients aged from 9 months to 15 years received voriconazole treatment for proven or suspected invasive fungal infections. This patient group included 34 patients aged 2–12 years and patients aged 12–15 years. Most patients (57 out of 61) had previously received antifungal agents without success. Five patients aged 12–15 years participated in therapeutic trials, while the remainder received voriconazole under other programs. The main underlying conditions in these patients included hematologic malignancies and aplastic anemia (27 patients) and chronic granulomatous disease (14 patients). The most common fungal disease was aspergillosis (43 out of 61 patients, 70%).

QTc interval study. A placebo-controlled, randomized, crossover single-dose study in healthy volunteers was conducted to assess the effect of investigational agents on the QTc interval. Three doses of oral voriconazole and ketoconazole were administered. The placebo-corrected mean maximum QTc prolongation from baseline was 5.1, 4.8, and 8.2 ms after administration of 800, 1200, and 1600 mg of voriconazole, respectively, and 7.0 ms after administration of 800 mg of ketoconazole. No study participant had a QTc interval 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, in specific patient groups, and in 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 hematologic and lymphoid malignancies), the investigated pharmacokinetic characteristics—namely, 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 has been estimated that increasing the oral dose from 200 mg to 300 mg twice daily results in an average 2.5-fold increase in exposure (AUCτ). An oral loading dose of 200 mg (or 100 mg for patients with body weight below 40 kg) achieves exposure equivalent to 3 mg/kg administered intravenously. An oral loading dose of 300 mg (or 150 mg for patients with body weight below 40 kg) achieves exposure equivalent to 4 mg/kg administered intravenously. When oral or intravenous loading doses are administered, plasma concentrations close to steady-state are achieved within the first 24 hours of therapy. Without a loading dose regimen, with repeated twice-daily administration of voriconazole, accumulation and steady-state plasma concentrations are generally achieved by day 6.

Absorption. Voriconazole is rapidly and almost completely absorbed after oral administration, with Cmax reached within 1–2 hours after dosing. Absolute bioavailability after oral administration is 96%. When voriconazole is administered repeatedly with a high-fat meal, Cmax and AUCτ are reduced by 34% and 24%, respectively. Changes in gastric pH do not affect voriconazole absorption.

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

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

In vivo studies 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 35%. Studies conducted in healthy Caucasian and Japanese volunteers demonstrated that exposure (AUCτ) in "slow metabolizers" of voriconazole is on average 4 times higher than in the comparator group of homozygous "rapid metabolizers." Heterozygous "rapid metabolizers" have on average 2 times higher exposure than homozygous "rapid metabolizers."

The main metabolite of voriconazole is 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, with less than 2% of the administered dose excreted unchanged in urine.

After administration of radiolabeled voriconazole, approximately 80% of radioactivity was recovered in urine 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 depends on dose and is approximately 6 hours after an oral 200 mg dose. Due to non-linear pharmacokinetics, half-life is not used to assess accumulation or elimination of voriconazole.

Pharmacokinetics in special patient populations.

Gender. In a multiple-dose oral voriconazole study, Cmax and AUCτ levels 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). 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).

Dose adjustment was not performed based on age in the program. A relationship between plasma concentration and age was observed. Safety profiles of voriconazole in young and elderly patients were similar; therefore, dose adjustment in elderly patients is not required (see section "Dosage and administration").

Pediatric population. The recommended oral dose for children is based on pharmacokinetic analysis of data from 112 immunocompromised children aged 2–12 years and 26 immunocompromised children aged 12–17 years. Multiple doses of 3, 4, 6, 7, and 8 mg/kg twice daily intravenously and multiple oral doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily (powder for oral suspension) were evaluated in 3 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 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. AUCτ 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. AUCτ in children after an oral maintenance dose of 9 mg/kg (maximum 350 mg) twice daily was comparable to AUCτ in adults after an oral dose of 200 mg twice daily. Exposure after an intravenous dose of 8 mg/kg is twice higher than 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. 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 the same dosing regimen. However, lower exposure was observed in some older children with low body weight, likely because their voriconazole metabolism resembles that of younger children rather than adults. Based on population pharmacokinetic analysis, children aged 12–14 years with body weight less than 50 kg should receive pediatric dosing (see section "Dosage and administration").

Renal impairment. In a study administering a single 200 mg dose 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 severity of renal impairment had minimal effect on voriconazole pharmacokinetics. Protein binding of voriconazole in plasma was similar across patients with varying degrees of renal impairment (see sections "Dosage and administration" and "Special precautions").

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

In a multiple-dose oral study, AUCτ was similar in patients with moderate liver 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 liver cirrhosis (Child–Pugh class C) are lacking (see sections "Dosage and administration" and "Special precautions").

Clinical characteristics.

Indications.

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

Voriconazole is indicated in adults and children aged 2 years and older 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 ZENTIVA should be used as initial therapy in patients with progressive or potentially life-threatening fungal infections.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, or ivabradine, as increased plasma concentrations of these 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, or phenobarbital, as these medicinal products may 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 efavirenz plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"); for use of lower efavirenz doses, see section "Special precautions for use").
• Concomitant use with high-dose ritonavir (400 mg or higher twice daily), as such ritonavir doses lead to a significant reduction in voriconazole plasma concentrations in healthy volunteers (for lower ritonavir doses, see section "Special precautions for use").
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as increased plasma concentrations of these agents may 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) (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 tumor 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 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 magnitude of AUC increase depends on the substrate (see table below).

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

Voriconazole should be used with caution in patients receiving other medicinal products that prolong the QTc interval. Since voriconazole has the potential to increase plasma concentrations of substances metabolized by CYP3A4 isoenzymes (e.g., certain antihistamines, quinidine, cisapride, pimozide, and ivabradine), concomitant use of these agents is contraindicated.

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 interaction; AUCτ – area under the concentration-time curve over the dosing interval; AUCt – area under the concentration-time curve from time zero to a specified time point; AUC0–∞ – area under the concentration-time curve from time zero to infinity; n/a – not applicable.

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

Table 6

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 interval prolongation and rarely to the development of ventricular tachycardia of the "torsades 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* 300 mg once daily with 400 mg voriconazole twice daily*	Cmax of efavirenz ↑ 38 % AUCτ of efavirenz ↑ 44 % Cmax of voriconazole ↓ 61 % AUCτ of voriconazole ↓ 77 % Compared to 600 mg efavirenz once daily: Cmax of efavirenz ↔ AUCτ of efavirenz ↑ 17 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 23 % AUCτ of voriconazole ↓ 7 %	Concomitant use of standard doses of voriconazole with efavirenz 400 mg once daily or higher is contraindicated (see section "Contraindications") When voriconazole and efavirenz are used concomitantly, the maintenance dose of voriconazole should be increased to 400 mg twice daily, and the dose of efavirenz should be reduced to 300 mg once daily. After discontinuation of voriconazole, the original efavirenz dose should be resumed (see sections "Dosage and administration" and "Special warnings and precautions for use")
Ergot alkaloids, e.g. ergotamine and dihydroergotamine (CYP3A4 substrates)	Although appropriate studies have not been conducted, voriconazole may increase plasma concentrations of ergot alkaloids and lead to ergotism	Contraindicated (see section "Contraindications")
Rifabutin (potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitant with voriconazole 350 mg twice daily*) 300 mg once daily (concomitant with voriconazole 400 mg twice daily*)	Cmax of voriconazole ↓ 69 % AUCτ of voriconazole ↓ 78 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↓ 4 % AUCτ of voriconazole ↓ 32 % Cmax of rifabutin ↑ 195 % AUCτ of rifabutin ↑ 331 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 104 % AUCτ of voriconazole ↑ 87 %	Concomitant use of voriconazole and rifabutin should be avoided unless benefit outweighs risk. The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight below 40 kg) (see section "Dosage and administration"). When rifabutin and voriconazole are used concomitantly, careful monitoring of complete blood counts and rifabutin-related adverse reactions (such as uveitis) is recommended
Rifampicin (potent CYP450 inducer) 600 mg once daily	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 with high doses of ritonavir (400 mg or higher twice daily) is contraindicated (see section "Contraindications"). Concomitant use of voriconazole with low doses of ritonavir (100 mg twice daily) should be avoided unless benefit outweighs risk
Venetoclax (CYP3A substrate)	Although studies have not been conducted, 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 of venetoclax (see section "Contraindications"). Dose reduction of venetoclax, as specified in the venetoclax prescribing information, is required during stable daily dosing; careful monitoring for signs of toxicity is recommended.
St. John's wort (CYP450 inducer; P-glycoprotein inducer) 300 mg three times daily (concomitant with single dose of 400 mg voriconazole)	In an independent published study, AUC0-∞ of voriconazole ↓ 59 %	Contraindicated (see section "Contraindications")
Everolimus (CYP3A4 substrate, P-glycoprotein substrate)	Although appropriate studies have not been conducted, voriconazole is known to cause significant increase in everolimus plasma concentration	Concomitant use of everolimus and voriconazole is not recommended, as voriconazole may cause significant increase in everolimus concentration
Naloxegol (CYP3A4 substrate)	Although studies have not been conducted, voriconazole is likely to cause significant increase in naloxegol plasma concentration	Concomitant use of voriconazole and naloxegol is not recommended due to insufficient data to provide clear dosing guidance in this situation (see section "Special warnings and precautions for use")
Fluconazole 200 mg once daily (inhibitor of CYP2C9, CYP2C19 and CYP3A4)	Cmax of voriconazole ↑ 57 % AUCτ of voriconazole ↑ 79 % Cmax of fluconazole – n/k AUCτ of fluconazole – n/k	It has not been established what dose reduction and/or frequency adjustment of voriconazole and fluconazole is necessary to avoid this effect. When voriconazole is administered after fluconazole, monitoring for voriconazole-related adverse reactions is recommended
Phenytoin (CYP2C9 substrate and potent CYP450 inducer) 300 mg once daily 300 mg once daily (concomitant with 400 mg voriconazole twice daily)*	Cmax of voriconazole ↓ 49 % AUCτ of voriconazole ↓ 69 % Cmax of phenytoin ↑ 67 % AUCτ of phenytoin ↑ 81 % Compared to 200 mg voriconazole twice daily: Cmax of voriconazole ↑ 34 % AUCτ of voriconazole ↑ 39 %	Concomitant use of voriconazole and phenytoin should be avoided unless benefit outweighs risk. When phenytoin and voriconazole are used concomitantly, 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)	Voriconazole Cmax ↓ 39 % Voriconazole AUC0-12 ↓ 44 % Voriconazole C12 ↓ 51 %	If concomitant use of voriconazole with letermovir is necessary, monitor for reduced efficacy of voriconazole
Anticoagulants Warfarin (CYP2C9 substrate) (single 30 mg dose of warfarin concomitant with 300 mg voriconazole twice daily) Other oral coumarins, such as phenprocoumon, acenocoumarol (CYP2C9 and CYP3A4 substrates)	Maximum prothrombin time approximately doubled Although appropriate studies have not been conducted, voriconazole is known to increase plasma concentrations of coumarins and thereby prolong prothrombin time	Close monitoring of prothrombin time and other appropriate coagulation parameters is recommended, with appropriate adjustment of anticoagulant doses
Ivacaftor (CYP3A4 substrate)	Interaction between voriconazole and ivacaftor has not been studied, but increased plasma concentration of ivacaftor is likely, which may increase the risk of adverse reactions	Dose reduction of ivacaftor is recommended
Benzodiazepines, e.g. midazolam, triazolam, alprazolam (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole is expected to increase plasma concentrations of benzodiazepines metabolized by CYP3A4 and prolong sedative effect	Consideration should be given to reducing the dose of benzodiazepines
Tolvaptan (CYP3A substrate)	Interaction with voriconazole has not been studied, but it is likely that voriconazole significantly increases tolvaptan plasma concentration	If concomitant use of voriconazole with tolvaptan is necessary, the dose of tolvaptan should be reduced
Immunosuppressants (CYP3A4 substrates) Sirolimus single 2 mg dose 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 Cmax of cyclosporine ↑ 13 % AUCτ of cyclosporine ↑ 70 % Cmax of tacrolimus ↑ 117 % AUCt of tacrolimus ↑ 221 %	Concomitant use is contraindicated (see section "Contraindications") For patients already receiving cyclosporine at the start of voriconazole therapy, a 50 % reduction in cyclosporine dose and close monitoring of cyclosporine 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 as needed For patients already receiving tacrolimus at the start of voriconazole therapy, a reduction in tacrolimus dose to one-third of the initial dose and close monitoring of tacrolimus levels are recommended. Elevated tacrolimus levels are associated with nephrotoxic effects. After discontinuation of voriconazole, tacrolimus levels should be closely monitored and the dose increased as indicated
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	Consideration should be given to reducing the dose of oxycodone and other CYP3A4-metabolized long-acting opioids (e.g. hydrocodone). Close and 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 elevated methadone plasma concentrations, including QT interval prolongation, is recommended. Dose reduction of methadone may be necessary
Non-steroidal 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 signs of toxicity is recommended. Dose adjustment of NSAIDs 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. For patients already receiving omeprazole (40 mg or higher) at the start of voriconazole therapy, 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, concomitant 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	Consideration should be given to reducing the dose of alfentanil, fentanyl, and other structurally similar CYP3A4-metabolized short-acting opioids (e.g. sufentanil). 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 capable of increasing plasma levels of CYP3A4-metabolized statins, potentially leading to rhabdomyolysis	Consideration should be given to reducing the statin dose
Sulfonylurea derivatives, e.g. tolbutamide, glipizide, glyburide (CYP2C9 substrates)	Although appropriate studies have not been conducted, voriconazole may increase plasma levels of sulfonylurea derivatives and thereby cause hypoglycemia	Close monitoring of blood glucose levels is required. Consideration should be given to reducing the dose of sulfonylurea derivatives
Vinca alkaloids, e.g. vincristine and vinblastine (CYP3A4 substrates)	Although appropriate clinical studies have not been conducted, voriconazole is known to increase plasma levels of vinca alkaloids and lead to neurotoxic effects	Consideration should be given to reducing the dose of vinca alkaloids
Other HIV protease inhibitors, e.g. 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 any signs of toxicity 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 also be induced by NNRTIs	Close monitoring for any signs of toxicity or lack of efficacy of these agents is recommended, along with consideration of dose adjustment
Cimetidine (non-specific CYP450 inhibitor and increases gastric 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
Mycophenolic acid (substrate of UGT 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 receiving long-term voriconazole and corticosteroid therapy (including inhaled corticosteroids, e.g. budesonide, and intranasal corticosteroids) should be closely monitored for adrenal insufficiency during and after discontinuation of voriconazole (see section "Special warnings and precautions for use").
Ranitidine (increases gastric pH) 150 mg twice daily	Cmax and AUCτ of voriconazole ↔	No dose adjustment required
Flucloxacillin [CYP450 inducer]	Significant reduction in voriconazole plasma concentration has been reported.	If concomitant use of voriconazole with flucloxacillin cannot be avoided, monitoring for potential loss of voriconazole efficacy (e.g. via therapeutic drug monitoring) is recommended; dose increase of voriconazole may be necessary.

Special precautions for use.

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

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 with heart failure;
• sinus bradycardia;
• presence of symptomatic arrhythmias;
• concomitant use of drugs that may prolong the QTc interval.

Electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia should be monitored and corrected as necessary before initiating and during treatment with voriconazole. A study in healthy volunteers assessed the effect of single doses of voriconazole up to 4 times the standard daily dose on the QTc interval. In none of the study participants did the 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, some with fatal outcomes) were infrequently observed with voriconazole use. Hepatic reactions occurred primarily in patients with severe underlying diseases (especially hematological malignancies). Transient hepatic reactions, including hepatitis and jaundice, were observed in patients without other identified risk factors. Liver function abnormalities were reversible and usually normalized after discontinuation of therapy (see section "Side effects").

Liver function monitoring. Patients receiving voriconazole should be regularly monitored for hepatotoxicity. Monitoring should include laboratory assessment of liver function (particularly aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) at the start of treatment and at least once weekly during the first month of therapy. The duration of treatment should be as short as possible; however, if continued based on risk-benefit assessment, the frequency of monitoring may be reduced to once monthly provided liver test results remain stable.

If liver test results show significant elevation, voriconazole should be discontinued, except when continuation is deemed necessary after medical evaluation of the risk-benefit ratio.

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

Serious skin-related adverse reactions.

• Phototoxicity. Voriconazole use has been additionally associated with phototoxic reactions such as freckles, lentigo, actinic keratosis, and pseudoporphyria. There is a potentially increased risk of skin reactions/toxicity when phototoxic agents (e.g., methotrexate, etc.) are used concomitantly. 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 (including Bowen’s disease). Among patients who developed squamous cell carcinoma of the skin were those who previously experienced phototoxic reactions. In case of phototoxic reactions, multidisciplinary physician consultations should be conducted, voriconazole therapy discontinued, consideration given to alternative antifungal agents, and the patient referred to a dermatologist. If voriconazole treatment continues, a dermatologist should systematically and regularly examine the patient for early detection and treatment of possible precancerous lesions. If precancerous skin lesions or squamous cell carcinoma are detected, voriconazole use must be discontinued (see section "Long-term therapy" below).
• Severe skin-related adverse reactions. Cases of severe skin-related adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported during voriconazole use. Patients presenting with rash should be closely monitored, and voriconazole use discontinued if signs of disease progression occur.

Adrenal gland effects

Adrenal insufficiency has occurred in some patients due to use of other azoles (e.g., ketoconazole).

Reversible cases of adrenal insufficiency have been observed 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 therapy (see section "Interaction with other medicinal products and other forms of interaction").

Long-term therapy. If prolonged use of the drug (treatment or prophylaxis) beyond 180 days (6 months) is required, a careful benefit-risk assessment should be performed; the physician should consider the possibility of limiting voriconazole intake (see section "Method of administration and dosage" and "Pharmacodynamics").

The following serious adverse reactions have been reported in association with long-term voriconazole use.

Cases of squamous cell carcinoma of the skin have been reported in connection with long-term use of Voriconazole Zentiva.

In patients who underwent organ transplant surgery, non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been observed. If a patient develops skeletal pain and radiological signs indicate periostitis, multidisciplinary physician consultations should be conducted and discontinuation of Voriconazole Zentiva considered.

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

Renal adverse reactions. Acute renal failure has been reported in patients with severe underlying conditions during voriconazole therapy. Decreased renal function may occur with concomitant use of voriconazole and nephrotoxic drugs and/or in the presence of comorbid conditions (see section "Side effects").

Renal function monitoring. Monitoring for possible renal function impairment is necessary and should include assessment of laboratory parameters, particularly serum creatinine levels.

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

Children. The safety and efficacy of voriconazole use in children under 2 years of age have not been established (see section "Side effects" and "Pharmacodynamics"). VORICONAZOLE ZENTIVA is recommended for use in children aged 2 years and older. Increased liver enzyme levels have been observed more frequently in children (see section "Side effects"). Liver function monitoring is required for both adults and children. In patients aged 2–12 years, oral bioavailability of the drug may be limited due to malabsorption and very low body weight. Intravenous voriconazole is recommended for these patients.

Serious skin-related adverse reactions (including squamous cell carcinoma of the skin). The incidence of phototoxic reactions is higher in children. Since progression of squamous cell carcinoma has been reported, strict photoprotection measures are required for this patient group. Children who have experienced lesions leading to photoaging, such as lentiginosis and ephelides, should avoid sun exposure and receive dermatological follow-up even after completion of therapy. Prevention. In case of treatment-related adverse reactions (hepatotoxicity, severe skin reactions including phototoxicity and squamous cell carcinoma, severe or prolonged visual disturbances, and periostitis), discontinuation of voriconazole and initiation of alternative antifungal agents should be considered.

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

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

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

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate). Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless the benefit of voriconazole use outweighs the risk (see section "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 regarding dosage adjustment (see section "Interaction with other medicinal products and other forms of interaction").

Naloxegol (CYP3A4 substrate). Concomitant use of voriconazole and naloxegol is not recommended, as voriconazole is expected to significantly increase naloxegol concentrations. Currently, there is 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). Careful monitoring for methadone-related adverse reactions and toxicity (including QTc prolongation) is recommended when methadone and voriconazole are used concomitantly, as methadone levels increase with concomitant voriconazole use. Dose reduction of methadone may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Short-acting opioids (CYP3A4 substrates). When 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 fourfold with concomitant voriconazole use, and published data from one study indicate that concomitant fentanyl and voriconazole use resulted in increased 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 (inhibitor of CYP2C9, CYP2C19, and CYP3A4). 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 eliminate this effect. Monitoring for voriconazole-related adverse reactions is recommended when voriconazole is used immediately after fluconazole (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Lactose. The product contains lactose; therefore, it should not be used in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Sodium. This medicinal product contains less than 1 mmol/l sodium (23 mg) per tablet. Patients on a low-sodium diet should be informed that this medicinal product is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of voriconazole in pregnant women. Animal studies have demonstrated reproductive toxicity.

The potential risk for humans is unknown.

VORICONAZOLE ZENTIVA should not be used during pregnancy, except when the expected benefit to the woman 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 period. Excretion of voriconazole into breast milk has not been studied; therefore, breastfeeding should be discontinued during treatment with VORICONAZOLE ZENTIVA.

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

VORICONAZOLE ZENTIVA should be taken at least 1 hour before or after a meal.

Monitoring of electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia is required before starting treatment and during therapy, and any imbalances should be corrected as necessary (see section "Special Warnings and Precautions for Use").

Treatment.

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

Detailed dosage recommendations are provided in Table 7.

Table 7

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

* Including patients aged 15 years and older.

The duration of treatment should be as short as possible, depending on the clinical and mycological response of the patient. If treatment longer than 180 days (6 months) is necessary, a careful benefit-risk assessment should be performed.

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

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

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 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 (see Tables 4 and 5).

Duration of prophylaxis.

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

Use of voriconazole 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 selection when co-administered with other agents. Phenytoin may be co-administered with voriconazole provided the voriconazole maintenance dose is increased from 200 mg to 400 mg orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight less than 40 kg) (see sections "Special Warnings and Precautions for Use" 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 orally twice daily (from 100 mg to 200 mg orally twice daily in patients with body weight less than 40 kg) (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Efavirenz may be co-administered with voriconazole provided the voriconazole maintenance dose is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e., to 300 mg once daily. After discontinuation of voriconazole, the initial efavirenz dose should be resumed (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Elderly patients. No dose adjustment is necessary for elderly patients.

Patients with renal impairment. Renal impairment does not affect the pharmacokinetic properties of voriconazole following oral administration. No dose adjustment is required for patients with mild 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.

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

Studies 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 (AST, ALT, alkaline phosphatase, and total bilirubin more than 5 times the upper limit of normal) is limited.

The use of VORICONAZOLE ZENTIVA has been associated with elevated liver function test values and clinical signs of liver injury, such as jaundice; therefore, the drug should be used in patients with severe hepatic impairment only if 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 drug is indicated for use in children aged 2 years and older. The safety and efficacy of voriconazole in children under 2 years of age have not been established.

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

Table 8

Recommended treatment regimen

Dosing regimen	Intravenous	Oral
Loading doses (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 VORICONAZOLE ZENTIVA should only be considered after achieving significant clinical improvement. It should be noted that an intravenous dose of 8 mg/kg provides approximately twice the voriconazole exposure compared to an oral dose of 9 mg/kg.

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

Dose adjustment for children aged 2–12 years and for children 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 initial oral dose of 350 mg is being used). If the patient does not tolerate the treatment, the dose should be reduced by 1 mg/kg (or by 50 mg if the maximum initial oral dose of 350 mg is being used).

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

Information on the use of VORICONAZOLE ZENTIVA for prophylaxis in children is provided above.

Overdose.

Three cases of accidental overdose have been reported. All three cases occurred in children who received intravenous VORICONAZOLE ZENTIVA at doses up to 5 times higher than recommended. 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. In cases of overdose, hemodialysis may assist in the elimination of voriconazole from the body.

Adverse Reactions

The safety profile of voriconazole in adults is based on data from an integrated safety database encompassing over 2000 individuals (including 1603 adult patients who participated in therapeutic trials) and an additional 270 adult patients from prophylaxis trials. 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 include visual disturbance, 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 based on age, race, or gender.

Since most of the studies were open-label, all adverse reactions potentially causally related to the drug are listed below. Adverse reactions are based on pooled data from 1873 adult patients who participated in therapeutic (1603) and prophylaxis (270) trials. 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 (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency 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 (including 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, paresthesia, somnolence, dizziness
Uncommon: Brain edema, encephalopathy⁴, extrapyramidal disorders⁵, peripheral neuropathy, ataxia, hypesthesia, dysgeusia
Rare: Hepatic encephalopathy, Guillain-Barré syndrome, nystagmus

Eye disorders

Very common: Visual disturbance⁶
Common: Retinal hemorrhage
Uncommon: Optic nerve disorders⁷, optic disc edema⁸, ocular hypertensive crisis, diplopia, scleritis, blepharitis
Rare: Optic 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 ECG, supraventricular tachycardia
Rare: Torsades de pointes, complete atrioventricular block, bundle branch block, nodal rhythm

Vascular disorders

Common: Hypotension, phlebitis
Uncommon: Thrombophlebitis, lymphangitis

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnea⁹
Common: Acute respiratory distress syndrome, pulmonary edema

Gastrointestinal disorders

Very common: Diarrhea, vomiting, abdominal pain, nausea
Common: Cheilitis, dyspepsia, constipation, gingivitis
Uncommon: Peritonitis, pancreatitis, tongue 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, erythema, photosensitivity
Uncommon: Stevens-Johnson syndrome, purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema
Rare: Toxic epidermal necrolysis⁸, drug reaction with eosinophilia and systemic symptoms (DRESS)⁸, angioneurotic edema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug-induced toxicoderma
Frequency not known: Cutaneous lupus erythematosus*, melasma*, lentigo*

Musculoskeletal and connective tissue disorders

Common: Back pain
Uncommon: Arthritis
Uncommon: Periostitis*

Renal and urinary disorders

Common: Acute renal failure, hematuria
Uncommon: Renal tubular necrosis, proteinuria, nephritis

General disorders and administration site conditions

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

Investigations

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

* Adverse reactions identified after marketing authorization.

¹ Includes febrile neutropenia and neutropenia.
² Includes immune thrombocytopenic purpura.
³ Includes nuchal rigidity and tetany.
⁴ Includes hypoxic-ischemic encephalopathy and metabolic encephalopathy.
⁵ Includes akathisia and parkinsonism.
⁶ See section "Visual disturbance" under "Adverse Reactions".
⁷ Prolonged optic neuritis has been reported post-marketing (see section "Special warnings and precautions for use").
⁸ See section "Special warnings and precautions for use".
⁹ Includes dyspnea and exertional dyspnea.
¹⁰ Includes drug-induced liver injury, toxic hepatitis, hepatocellular injury, and hepatotoxicity.
¹¹ Includes periorbital edema, lip swelling, and oral cavity edema.

Description of selected adverse reactions

Eye disorders. Visual disturbance (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, visual disorders, presence of halos in the visual field, night blindness, oscillopsia, photopsia, flickering scotoma, decreased visual acuity, visual brightness, visual field defect, floaters in the vitreous body, and xanthopsia) was very commonly observed during clinical trials and was associated with voriconazole use. These visual disturbances were transient and spontaneously resolved within 60 minutes in most cases; no clinically significant long-term visual effects were observed. Symptoms generally diminished with repeated dosing. Visual disturbances were generally mild, rarely led to drug discontinuation, and were not associated with long-term sequelae. Visual disturbance may be related to high plasma concentrations and/or doses of the drug.

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 study evaluating its effect 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 visual adverse reactions; see section "Special warnings and precautions for use".

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

Patients should be closely monitored for skin reactions, and if lesions progress, treatment with VORICONAZOLE ZENTIVA should be discontinued.

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

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

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

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

Prophylaxis.

In a study comparing voriconazole and 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 in the voriconazole group compared to 39.6% in the itraconazole group. Treatment-related hepatic adverse reactions led to permanent discontinuation of the study drug in 50 patients (21.4%) receiving voriconazole and in 18 patients (7.1%) receiving itraconazole.

Pediatric population. The safety of voriconazole was evaluated in 288 children aged 2–12 years (169) and 12–18 years (119), who received voriconazole for prophylaxis (183) or treatment (105) in clinical trials. Safety was also assessed in 158 children aged 2–12 years through compassionate-use programs. Overall, the safety profile in children was similar to that in adults. However, there was a trend toward more frequent elevation of liver enzymes in children compared to adults (incidence of transaminase elevation was 14.2% in children vs. 5.3% in adults), reported as an adverse reaction in clinical trials. Post-marketing experience suggests that the frequency of skin reactions (particularly erythema) may be slightly higher in children than in adults. In 22 patients under 2 years of age treated 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). Cases of pancreatitis in children have also been reported during post-marketing use.

Reporting suspected adverse reactions. Reporting 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.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.
Keep out of the reach of children.

Packaging.

7 tablets in a PVC/aluminum blister. 2 or 4 blisters per cardboard box.

10 tablets in a PVC/aluminum blister. 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturers.

Farmaten S.A.
Farmaten International S.A.

Manufacturer's address and place of business.

6, Dervenakion, Pallini Attiki, 15351, Greece
Industrial Park Sapes, Prefecture of Rodopi, Block No. 5, Rodopi, 69300, Greece

Marketing authorization holder.

Zentiva k.s.

Address of marketing authorization holder.

Dolni Měcholupy, U kabelovny 130, 10237 Prague 10, Czech Republic