Expiration date: 01/2025

Active substances: Voriconazole

Release form 3.4 g - vials (1) - cardboard packs.

Country of origin/France

Productionfarmation and Upjohn Campaign/ Fareva Amboise

Keep away from children

Dosage form

Lyophilizate for the preparation of a solution for infusions of white color

Composition

Voriconazole 200 mg

Excipients: sodium salt of beta-cyclodextrin sulfobutyl ether (SBECD).

Pharmacotherapeutic group

antifungal agent

Pharmacodynamics

A broad-spectrum antifungal drug from the triazole group. The mechanism of action is associated with the inhibition of demethylation of 14?-sterol mediated by fungal cytochrome P450, this reaction is a key step in the biosynthesis of ergosterol.

In vitro, voriconazole has a wide spectrum of antifungal action, is active against Candida spp. (including strains of Candida krusei resistant to fluconazole and resistant strains of Candida glabrata and Candida albicans) and has a fungicidal effect against all studied strains of Aspergillus spp., as well as pathogenic fungi that have become relevant recently, including Scedosporium or Fusarium, which are to a limited extent sensitive to antifungal agents.

The clinical efficacy of voriconazole has been demonstrated in infections caused by Aspergillus spp. (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Aspergillus nidulans), Candida spp. (including strains of Candida albicans, Candida dubliniensis, Candida glabrata, Candida inconspicua, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida guillermondii), Scedosporium spp. (including Scedosporium apiospermum /Pseudoallescheria boydii/, Scedosporium prolifecans) and Fusarium spp.

Other fungal infections in which the drug was used (often with a partial or complete response) included isolated cases of infections caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidoides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. (including Penicillium marneffei), Philaphora richardsiae, Scopulariopsis brevicaulis and Trychosporon spp. (including Trychosporon beigelii).

Voriconazole activity has been demonstrated in vitro against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 to 2 micrograms/ml.

Voriconazole activity against Curvularia spp. and Sporothrix spp. was detected in vitro, but its clinical significance is unknown.

Pharmacokinetics

The pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

Distribution

The pharmacokinetics of voriconazole is nonlinear due to saturation of its metabolism. When the dose is increased, a disproportionate (more pronounced) increase in AUC is observed. With intravenous administration of shock doses, plasma concentrations approach equilibrium during the first 24 hours. If the drug is prescribed 2 in medium (not in shock) doses, then the accumulation of the drug occurs, and equilibrium concentrations are reached by day 6 in most patients

The calculated Vd of voriconazole in the equilibrium state is 4.6 l / kg, which indicates the active distribution of the drug in the tissue. Binding to plasma proteins is 58%.

Voriconazole penetrates through the BBB and is detected in the cerebrospinal fluid.

Metabolism and excretion

According to in vitro studies, voriconazole is metabolized by the action of hepatic cytochrome P450 isoenzymes - CYP2C19, CYP2C9, CYP3A4, while 2C19 plays an important role in the metabolism of voriconazole. This enzyme exhibits a pronounced genetic polymorphism, and therefore a reduced metabolism of voriconazole is possible in 15-20% of patients of Asian origin and in 3-5% of patients of Caucasian and Negroid races. Studies in representatives of the Caucasian race and Japanese have shown that in patients with reduced metabolism, the AUC of voriconazole is on average 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with active metabolism, the AUC of voriconazole is on average 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide (72% of the metabolites circulating in plasma labeled with a radioactive label). This metabolite has minimal antifungal activity.

Unchanged, less than 2% of the administered dose of the drug is excreted in the urine.

After repeated intravenous administration, approximately 83% and 80% of the dose (of a drug with a radioactive label) are detected in the urine, respectively. Most (>94%) of the total dose is excreted during the first 96 hours after intravenous administration.

Due to the nonlinearity of pharmacokinetics, the T1/2 value does not allow to predict the accumulation or elimination of voriconazole.

Pharmacokinetics in special clinical cases

Gender and age. There is no need to adjust the dose depending on gender. Plasma concentrations in men and women are similar. The safety of voriconazole in young and elderly patients is the same, and therefore dose adjustment when used in elderly patients is not required.

Impaired renal function. Binding to plasma proteins is similar in patients with varying degrees of renal insufficiency. In patients with moderate or severe renal impairment (serum creatinine level ?220 mmol /l or 2.5 mg / dl), accumulation of an auxiliary substance (SBECD), which is part of the lyophilizate for the preparation of a solution for injection, is observed.

Indications

• invasive aspergillosis;
• severe invasive forms of candida infections (including Candida krusei);
• candidiasis of the esophagus;
• severe fungal infections caused by Scedosporium spp. and Fusarium spp.;
• severe fungal infections with intolerance or refractoriness to other medicines;
• prevention of breakthrough fungal infections in patients with fever from high-risk groups (recipients of allogeneic bone marrow, patients with recurrent leukemia).

Contraindications

• simultaneous administration of CYP3A4 substrates – terfenadine, astemizole, cisapride, pimozide and quinidine;
• simultaneous reception of sirolimus;
• simultaneous administration with rifampicin, carbamazepine and long-acting barbiturates;
• simultaneous administration with ritonavir;
• simultaneous administration with efavirenz;
• simultaneous administration with ergot alkaloids (ergotamine, dihydroergotamine);
• hypersensitivity to the components of the drug;

With caution, the drug is prescribed to patients with severe hepatic insufficiency, with severe renal insufficiency, as well as with hypersensitivity to other drugs – azole derivatives. Safety and efficacy in children under 2 years of age have not been established

Method of administration and dosage

Parenterally, Vfend® is administered only as an infusion at a rate of no more than 3 mg / kg / h for 1-2 hours. The solution cannot be injected in / in a jet.

For adults, Vfend® is prescribed intravenously on the first day at the recommended saturating dose in order to achieve a concentration of voriconazole in blood plasma close to equilibrium on the first day of therapy.

Given the high bioavailability of the drug when taken orally (96%), in the presence of clinical indications, a transition from parenteral administration to oral administration is possible

Dose selection

If the effectiveness of the therapy is insufficient, the maintenance dose for intravenous administration can be increased to 4 mg / kg every 12 hours.

If the drug is intolerant at this higher dose, it is reduced to 3 mg / kg every 12 hours.

When used simultaneously with rifabutin or phenytoin, the maintenance dose of Vfend for intravenous administration is increased to 5 mg / kg every 12 hours.

The duration of therapy depends on the clinical effect and the results of mycological examination.

Correction of the dosage regimen in elderly patients is not required.

When prescribing Vfend in the form of an infusion, it should be borne in mind that in patients with moderate or severe renal impairment (CC less than 50 ml / min), the accumulation of an auxiliary substance (SBECD) occurs. In this category of patients, Vfend® should be administered orally, except in cases where the intended benefit exceeds the potential risk, while it is necessary to regularly monitor creatinine levels, in case of its increase, the possibility of switching to taking the drug orally should be discussed.

Side effects

From the body as a whole: very often – fever, peripheral edema; often – chills, asthenia, chest pain, reactions and inflammation at the injection site, flu-like syndrome.

From the cardiovascular system: often – a decrease in blood pressure, thrombophlebitis, phlebitis; rarely – atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias, prolongation of the QT interval, ventricular fibrillation; very rarely – ventricular tachycardia (including ventricular flutter), complete AV block, blockage of the bundle of Gis, nodular arrhythmias.

From the digestive system: very often – nausea, vomiting, diarrhea, abdominal pain; often – increased activity of ALT, AST, alkaline phosphatase, LDH, GGT and bilirubin levels in blood plasma, jaundice, cheilitis, gastroenteritis, cholestasis; rarely – cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, swelling of the tongue, peritonitis; very rarely – pseudomembranous colitis, hepatic coma. The overall frequency of clinically significant increase in transaminase activity is 13.4%. Liver dysfunction may be associated with higher plasma concentrations or doses of the drug and in most cases disappear with the continuation of therapy (without changing the dose or after its correction) or with its cancellation. In patients with serious underlying diseases (malignant hematological diseases), cases of severe hepatotoxicity were rarely observed against the background of the use of voriconazole

Drug interaction

Voriconazole is metabolized by the isoenzymes CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes can cause, respectively, an increase or decrease in voriconazole concentrations in plasma.

Combinations in which there is a significant decrease in the concentration of voriconazole in blood plasma

When used concomitantly with rifampicin (CYP450 inducer) at a dose of 600 mg / Cmax and AUC of voriconazole are reduced by 93% and 96%, respectively (this combination is contraindicated).

When used in combination with powerful CYP450 inducers carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in the Cmax of voriconazole in plasma is possible, although their interaction has not been studied (such combinations are contraindicated).

Combinations in which no dose adjustment of voriconazole is required

When combined with cimetidine (a non-specific CYP450 inhibitor) at a dose of 400 mg, 2 Cmax and AUC of voriconazole increase by 18% and 23%, respectively.

Special instructions

Before starting therapy, it is necessary to correct such electrolyte disorders as hypokalemia, hypomagnesemia and hypocalcemia.

Sampling for culture and other laboratory studies (serological, histopathological) in order to isolate and identify pathogens should be carried out before the start of treatment. Therapy can be started before receiving the results of laboratory tests, and then adjusted if necessary. Clinical strains with reduced sensitivity to voriconazole have been identified. However, elevated BMD does not always allow predicting clinical inefficiency: there are cases when voriconazole was effective in infections caused by microorganisms resistant to other azoles. It is difficult to assess the correlation between in vitro activity and clinical results of treatment, given the complexity of patients who were included in clinical studies; the values of the borderline concentrations of voriconazole, allowing to assess sensitivity to this drug, have not been established.

Adverse reactions from the cardiovascular system

The use of voriconazole can lead to an extension of the QT interval on the ECG, which is accompanied by rare cases of ventricular flutter in patients with multiple risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of adverse events from the cardiovascular system). In patients with these potentially proarrhythmic conditions, voriconazole should be administered with caution

Hepatotoxicity

Adverse events from the liver, observed during the treatment with voriconazole, mainly appeared in patients with serious diseases (mainly malignant blood tumors). Transient liver reactions, including hepatitis and jaundice, are observed in patients without any risk factors. Liver dysfunction is usually reversible and resolves after discontinuation of treatment. During treatment with voriconazole, liver function should be regularly monitored (including liver tests and bilirubin levels). If clinical signs of liver disease appear, the expediency of discontinuing therapy should be discussed.

Adverse reactions from the kidneys

In severe patients receiving voriconazole and other nephrotoxic drugs and having concomitant diseases, cases of acute renal failure were observed. During the period of use of the drug, it is necessary to monitor the indicators of kidney function (including the level of creatinine in the blood serum).

Infusion reactions

With pronounced infusion reactions, the expediency of continuing the infusion of Vfend should be discussed.

Dermatological reactions

With the progression of dermatological reactions, the drug should be discontinued. Patients using Vfend® should avoid exposure to the sun and UV radiation.

Phenytoin

If necessary, the combined use of Vfend and phenytoin should be carefully evaluated

Storage temperature

from 2? to 30?