Voriconazole Rompharm lyophilisate for concentrate for solution for infusion 200 mg vial No. 1

Instructions for use Voriconazole Rompharm lyophilisate for concentrate for solution for infusion 200 mg vial No. 1

Composition

active ingredient: voriconazole;

1 vial contains 200 mg of voriconazole;

excipient: sodium sulfobutylbetadex.

Dosage form

Lyophilisate for concentrate for solution for infusion.

Main physicochemical properties: white to almost white powder.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Voriconazole is a triazole antifungal agent. The primary mechanism of action is inhibition of the fungal cytochrome P450-mediated demethylation of 14α-lanosterol, a key step in ergosterol biosynthesis. Accumulation of 14α-methylsterol correlates with subsequent loss of ergosterol from fungal cell membranes and may be responsible 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 mammals.

Pharmacokinetics/pharmacodynamics.

In 10 therapeutic studies, the median mean 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 mean, maximum, or minimum plasma concentrations of voriconazole and efficacy was not established in therapeutic studies, and such a relationship was not demonstrated in prevention studies.

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

Clinical efficacy and safety

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

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

Other fungal infections, often with both partial and 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 strains was observed for various species of Acremonium, Alternaria, Bipolaris, Cladophialophora, Histoplasma capsulatum, with inhibition of most strains occurring at voriconazole concentrations ranging from 0.05 to 2 μg/mL.

The drug has been demonstrated to have in vitro activity against various species of Curvularia and various species of Sporothrix, but the clinical significance of this activity has not yet been elucidated.

Checkpoints

Before initiating therapy, fungal culture specimens and other appropriate laboratory tests (serology, histopathology) should be obtained to isolate and identify the pathogenic microorganisms responsible for the infection. Therapy may be initiated before the results of culture and laboratory tests are known; however, as soon as the results of these tests become available, etiotropic therapy should be adjusted accordingly.

The species most commonly causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei, all of which have a minimum inhibitory concentration (MIC) of voriconazole of less than 1 mg/L.

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

EUCAST defined limits

Clinical experience of use

For the purposes of this section, a satisfactory response to the drug is defined as a complete or partial response.

Aspergillus infections: efficacy in patients with aspergillosis with poor prognosis

Voriconazole exhibits in vitro fungicidal activity against various Aspergillus species. The efficacy and survival benefits of voriconazole compared with the standard drug amphotericin B as first-line therapy for acute invasive aspergillosis were demonstrated in an open-label, randomized, multicenter study of 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously at a loading dose of 6 mg/kg every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours for 7 days. The route of administration could then be changed to oral administration at a dose of 200 mg every 12 hours. The median duration of intravenous voriconazole therapy was 10 days (range, 2–85 days). After intravenous therapy, the median duration of oral voriconazole use was 76 days (2–232 days).

A satisfactory overall response (complete or partial resolution of all associated symptoms, signs, and radiographic/bronchoscopic changes present at baseline) was observed in 53% of patients receiving voriconazole compared with 31% of patients receiving the comparator. The 84-day survival rate of patients receiving voriconazole was statistically significantly higher than that of the comparator, and voriconazole demonstrated clinically and statistically significant advantages in terms of both time to death and time to withdrawal due to toxicity. This study confirmed the results of a previous prospective study that had shown a positive effect in patients with risk factors for poor prognosis, including graft-versus-host disease and, in particular, cerebral infections (usually associated with 100% mortality). In these studies, the drug was studied in the treatment of paranasal sinus aspergillosis, cerebral, pulmonary and disseminated aspergillosis in patients after bone marrow and solid organ transplantation, in patients with malignant blood diseases, malignant tumors and AIDS.

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

In a secondary analysis using the Study Data Monitoring Committee assessments at the last evaluable time point (end of therapy or 2, 6, or 12 weeks after end of therapy), the response rates to voriconazole and amphotericin B followed by fluconazole were 65% and 71%, respectively.

The investigator-assessed incidence of favorable treatment outcome at each of these evaluable time points is shown in the table below.

Severe refractory infections caused by Candida species

A clinical study was conducted in 55 patients with severe refractory systemic infections caused by Candida species (including candidemia, disseminated candidiasis, and other forms of invasive candidiasis) who had failed prior antifungal therapy, including fluconazole. A favorable response to voriconazole treatment was observed in 24 patients (15 complete responses, 9 partial responses). In patients infected with fluconazole-resistant strains other than Candida albicans, a favorable outcome of voriconazole treatment was observed in 3 of 3 patients infected with C. krusei (all complete responses) and in 6 of 8 patients infected with C. glabrata (5 complete responses, 1 partial response). The clinical efficacy data were supported by limited data on the determination of the susceptibility of the pathogens to the drug.

Infections caused by various species of Scedosporium and Fusarium

Voriconazole has been shown to be effective against the following rare pathogenic fungi:

• Scedosporium species: A favorable response to voriconazole therapy was observed in 16 of 28 patients infected with S. apiospermum (6 patients had a complete response, 10 had a partial response), and in 2 of 7 patients infected with S. prolificans (both had a partial response). In addition, a favorable response was observed in 1 of 3 patients infected with more than one pathogen, including different Scedosporium species;
• Fusarium species: 7 of 17 patients responded to voriconazole (3 complete, 4 partial responses). 3 of 7 patients had ocular infection, 1 had paranasal sinus infection, and 3 had disseminated infection. An additional 4 patients with Fusarium were infected with multiple pathogens; 2 of these patients responded favorably.

Most patients treated with voriconazole for the above rare infections had intolerance or resistance to previously used antifungal agents.

Voriconazole was compared with itraconazole as primary prophylaxis in an open-label, comparative, multicenter study in adult and adolescent allogeneic hematopoietic stem cell transplant recipients without prior confirmed or suspected invasive fungal infection. Success was defined as the ability to provide prophylaxis with study drug for 100 days after hematopoietic stem cell transplant (continuously for > 14 days) and survival without prior confirmed or suspected invasive fungal infection for 180 days after hematopoietic stem cell transplant. The modified “intent-to-treat” (ITT) group included 465 allogeneic hematopoietic stem cell transplant recipients, of whom 45% had acute myeloid leukemia. Of all patients, 58% were receiving myeloablative regimens. Study drug prophylaxis was initiated immediately after hematopoietic stem cell transplantation: 224 patients received voriconazole and 241 patients received itraconazole. The median duration of study drug prophylaxis in the ITT group was 96 days for voriconazole and 68 days for itraconazole.

Efficacy ratios and other secondary endpoints are presented in the table below.

* Primary endpoint of the study.

** Difference in ratios, 95% CIs and P-values obtained after adjustment for randomization.

The rates of invasive fungal infection through day 180 and the primary endpoint of the study, i.e. “efficacy at day 180,” for patients with acute myeloid leukemia and conditioning, respectively, are presented in the table below.

Acute myeloid leukemia

* Primary endpoint of the study.

** Demonstrates at least 5% efficiency.

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

Myeloablative conditioning regimen

* Primary endpoint of the study.

** Demonstrates at least 5% efficiency.

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

Secondary prevention of invasive fungal infection: efficacy in hematopoietic stem cell transplant recipients with previously confirmed or suspected invasive fungal infection

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

Duration of therapy

In clinical trials, 705 patients received voriconazole for longer than 12 weeks and 164 patients received voriconazole for longer than 6 months.

Children

Fifty-three pediatric patients 2 to 18 years of age were treated with voriconazole in two prospective, open-label, non-comparative, multicenter clinical trials. One trial included 31 patients with possible, confirmed, or probable invasive aspergillosis, of whom 14 patients had confirmed or probable invasive aspergillosis. These patients were included in the efficacy analyses of the modified intent-to-treat population. The second trial included 22 patients with invasive candidiasis, including candidemia and esophageal candidiasis, who required primary or salvage therapy. Of these patients, 17 were included in the efficacy analyses of the modified intent-to-treat population. In patients with invasive aspergillosis, the overall overall response rate at 6 weeks was 64.3% (9 of 14); the overall response rate in patients aged 2 to 12 years was 40% (2 of 5) and in patients aged 12 to 18 years was 77.8% (7 of 9). In patients with candidemia, the overall response rate at the end of treatment was 85.7% (6 of 7) and in patients with esophageal candidiasis was 70% (7 of 10). The combined response rate (in patients with candidemia and esophageal candidiasis combined) was 88.9% (8 of 9) in patients aged 2 to 12 years and 62.5% (5 of 8) in patients aged 12 to 18 years.

Clinical studies on the determination of the QTc interval

A placebo-controlled, randomized, single-dose crossover study was conducted to evaluate the effects of study drugs on the QTc interval in healthy volunteers. Three doses of oral voriconazole and ketoconazole were administered. The placebo-adjusted mean maximum QTc prolongation from baseline was 5.1, 4.8, and 8.2 ms after 800, 1200, and 1600 mg of voriconazole, respectively, and 7.0 ms after 800 mg of ketoconazole. No subject had a QTc prolongation ≥ 60 ms from baseline. No subject exceeded the potentially clinically significant threshold of 500 ms.

Pharmacokinetics.

General pharmacokinetic characteristics

The pharmacokinetics of voriconazole have been studied in healthy volunteers, in special patient populations, and in patients. When administered orally at doses of 200 mg or 300 mg twice daily for 14 days in patients at increased risk of developing aspergillosis (mainly patients with malignant neoplasms of lymphatic and hematopoietic tissues), the pharmacokinetic characteristics studied, namely: rate and uniformity of absorption, cumulation, and nonlinearity of pharmacokinetics, were similar to those in healthy volunteers.

The pharmacokinetics of voriconazole are non-linear due to its extensive metabolism. With increasing dose, the increase in exposure is greater than proportional. It has been estimated that with oral administration, increasing the dose of the drug from 200 mg to 300 mg 2 times a day leads to an average increase in its exposure (AUCτ) of 2.5 times. An oral loading dose of 200 mg (or 100 mg for patients weighing less than 40 kg) achieves exposures corresponding to the administration of a dose of 3 mg/kg intravenously. An oral loading dose of 300 mg (or 150 mg for patients weighing less than 40 kg) achieves exposures corresponding to the administration of a dose of 4 mg/kg intravenously. When using loading doses of voriconazole orally or intravenously, its plasma concentrations, close to equilibrium, are achieved within the first 24 hours of therapy. If a loading dose regimen is not used, with repeated administration of voriconazole twice daily, in most patients its accumulation with achievement of equilibrium plasma concentrations occurs on the 6th day.

Absorption

Voriconazole is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) occurring 1–2 hours after administration. The absolute bioavailability of voriconazole following oral administration is 96%. When multiple doses of voriconazole were administered with a high-fat meal, Cmax and AUCτ were decreased by 34% and 24%, respectively. Changes in gastric pH do not affect the absorption of voriconazole.

Distribution

The volume of distribution of voriconazole at steady state is estimated to be 4.6 L/kg, indicating extensive tissue distribution. The plasma protein binding of voriconazole is estimated to be 58%. Voriconazole was identified in detectable amounts in all cerebrospinal fluid samples collected from 8 patients in a charitable research program.

In vitro studies have shown that voriconazole is metabolized by cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Voriconazole has high interindividual pharmacokinetic variability.

In vivo studies have shown that CYP2C19 plays a significant role in the metabolism of voriconazole. This enzyme is characterized by genetic polymorphism. For example, 15–20% of patients of the Mongoloid race can be expected to be poor metabolizers of this drug. Among representatives of the Caucasian and Negroid races, the number of individuals with poor metabolizers is 3–5%. Studies conducted in healthy volunteers of the Caucasian race and Japanese have shown that in the “poor metabolizers” of voriconazole, the drug exposure (AUCτ) is on average 4 times higher than in the comparison group — in the homozygous “extensive metabolizers” of voriconazole. Heterozygous “extensive metabolizers” of voriconazole have an average of 2 times higher exposure to the drug than in the comparison group — in the homozygous “extensive metabolizers”.

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

Excretion

Voriconazole is eliminated from the body by hepatic metabolism, with less than 2% of the administered dose excreted unchanged in the urine.

When radiolabeled voriconazole was administered, approximately 80% of the radioactivity was recovered in the urine after multiple intravenous doses and 83% after multiple oral doses. The majority (>94%) of the radioactivity was excreted within the first 96 hours after both intravenous and oral doses.

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

Pharmacokinetics in special patient groups

Gender. In a multiple-dose oral voriconazole study, Cmax and AUCτ in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18–45 years). In the same study, no statistically significant differences were observed between these parameters in healthy elderly men and women (≥ 65 years). No dose adjustment was made based on gender in the clinical program. The safety profiles and plasma concentrations of the drug were similar in women and men. Therefore, no dose adjustment is necessary based on gender.

Elderly patients: In a multiple-dose clinical study, Cmax and AUCτ 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).

No dose adjustment was made based on age in clinical studies. A relationship between plasma concentrations and age was observed. The safety profiles of voriconazole in young and elderly patients were similar, and no dose adjustment is necessary for elderly patients (see Dosage and Administration).

Children: The recommended oral dose in children is based on a pharmacokinetic analysis of data from 112 immunocompromised children aged 2 to 12 years and 26 immunocompromised children aged 12 to 17 years. Multiple doses of 3, 4, 6, 7, and 8 mg/kg twice daily intravenously and multiple doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily orally (powder for oral suspension) were evaluated in 3 pharmacokinetic studies in children. Loading doses of 6 mg/kg twice daily intravenously on the first day followed by subsequent doses of 4 mg/kg twice daily intravenously and 300 mg twice daily orally (tablets) were evaluated in one pharmacokinetic study in children. This category of patients showed more pronounced individual variability compared to adults.

The higher maintenance dose for intravenous administration in children than in adults reflects the greater elimination capacity due to the larger liver mass relative to body weight. When administered orally, the bioavailability of the drug may be reduced in children with malabsorption and very low body weight for their age. In such cases, intravenous administration of voriconazole is recommended.

Voriconazole exposure in most older children was comparable to that in adults at the same dosing regimen. However, some older children with low body weight had lower voriconazole exposure compared to adults. It appears that these patients have a similar metabolism of voriconazole to that in children, rather than adults. Based on a population pharmacokinetic analysis, children aged 12-14 years and weighing less than 50 kg should receive the pediatric dose (see section 4.2).

Renal impairment: In patients with moderate to severe renal impairment (serum creatinine >2.5 mg/dL), accumulation of β-cyclodextrin sulfobutyl ether sodium occurs (see sections 4.2 and 4.4).

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

In a multiple-dose oral clinical study, AUCτ was similar in patients with moderate cirrhosis (Child-Pugh B) receiving a maintenance dose of 100 mg twice daily and in patients with normal liver function receiving 200 mg twice daily. Pharmacokinetic data are not available in patients with severe cirrhosis (Child-Pugh C) (see Dosage and Administration and Precautions).

Indication

Prevention of invasive fungal infections in allogeneic bone marrow transplantation in patients at high risk of such a complication.

Voriconazole Rompharm is used in adults and children to treat:

• invasive aspergillosis;
• candidemia not accompanied by neutropenia;
• severe invasive infections caused by Candida (including C. krusei) resistant to fluconazole;
• severe fungal infections caused by Scedosporium and Fusarium species.

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

Contraindication

Hypersensitivity to voriconazole or to any of the excipients listed in section 6.1.

Concomitant administration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine or ivabradine, as increased plasma concentrations of these medicinal products may lead to QTc prolongation and rare cases of torsades de pointes (see section 4.5).

Concomitant administration with rifampicin, carbamazepine, phenobarbital and St. John's wort, as these drugs can significantly reduce the concentration of voriconazole in the blood plasma (see section "Interaction with other medicinal products and other types of interactions").

Co-administration of standard doses of voriconazole with efavirenz at doses of 400 mg once daily or higher is contraindicated, as efavirenz significantly decreases plasma concentrations of voriconazole in healthy subjects at these doses. Voriconazole also significantly increases plasma concentrations of efavirenz (see section 4.5; for lower doses, see section 4.4).

Co-administration with high-dose ritonavir (400 mg and above twice daily) - as ritonavir significantly reduces the plasma concentration of voriconazole in healthy subjects at this dose (see section "Interaction with other medicinal products and other types of interactions", for lower doses see section "Special warnings and precautions for use").

Concomitant administration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, as an increase in the concentration of these active substances in the blood plasma may lead to ergotism (see section "Interaction with other medicinal products and other types of interactions").

Concomitant administration with sirolimus, as voriconazole may significantly increase sirolimus plasma concentrations (see section “Interaction with other medicinal products and other forms of interaction”).

Co-administration of voriconazole with naloxegol, a CYP3A4 substrate, as increased plasma concentrations of naloxegol may precipitate opioid withdrawal symptoms (see section 4.4).