Vifend lyophilizate 200mg, vials 1pc

Composition

1 bottle of lyophilizate for preparation of infusion solution contains:

Active ingredient:

voriconazole 200 mg,

excipients:

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

Pharmacological action

Voriconazole is a broad-spectrum antifungal drug that belongs to the group of antibiotics of the triazole structure.

The mechanism of action of voriconazole is related to the inhibition of 14α-sterol demethylation mediated by fungal cytochrome P 450; this reaction is a key step in ergosterol biosynthesis.

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

Clinical efficacy has been demonstrated in infections caused by Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp. including C. albicans, C. dubliniensis, C. glabrata, C. inconspicua, C. krusei, C. parapsilosis, C. tropicalis and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

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

In vitro studies demonstrated the activity of voriconazole 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.

In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp. was detected, but its clinical significance is unknown.

Pharmacokinetics

The pharmacokinetics of voriconazole were studied in healthy people, representatives of special groups, and patients. The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. When the dose is increased, a disproportionate (more pronounced) increase in AUC (area under the concentration-time curve) is observed. It is estimated that an increase in the oral dose from 200 mg 2 times a day to 300 mg 2 times a day leads to an increase in AUCt by an average of 2.5 times. With intravenous or oral shock doses, plasma concentrations approach equilibrium within the first 24 hours. If the patient does not receive a shock dose, then with repeated use of voriconazole 2 times a day, the drug accumulates, and equilibrium plasma concentrations are reached by day 6 in most patients.

Voriconazole is rapidly and almost completely absorbed after oral use; maximum plasma concentrations (Cmax) are reached 1-2 hours after use. The oral bioavailability of voriconazole is 96%. When voriconazole is re-administered with fatty foods, Cmax and AUCt decrease by 34% and 24%, respectively.

The absorption of voriconazole does not depend on the pH of gastric juice.

The estimated volume of distribution of voriconazole at steady state is 4.6 l/kg, which indicates an active distribution of the drug in the tissue. Binding to plasma proteins is 58%.

Voriconazole is detected in the spinal fluid.

The pharmacokinetics of voriconazole are characterized by high interindividual variability. In vitro studies have shown that voriconazole is metabolized by hepatic cytochrome P 450 isoenzymes-CYP2C19, CYP2C9, and CYP3A4.

In vivo studies also suggest that CYP2C19 plays an important role in voriconazole metabolism. This enzyme exhibits a genetic polymorphism. For example, reduced voriconazole metabolism can be expected in 15-20% of Asians and 3-5% of whites and blacks. Studies in white and Japanese people have shown that patients with reduced metabolism have an average AUCt of voriconazole 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with active metabolism, the AUCt of voriconazole is on average 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide, which accounts for 72% of the circulating labeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole. Less than 2% of the drug dose is excreted unchanged in the urine.

After repeated intravenous and oral use of labeled voriconazole, approximately 80% and 83% of the radioactive dose, respectively, are detected in the urine. Most (>94%) of the total dose is eliminated within the first 96 hours after oral and intravenous use.

The terminal half-life of voriconazole depends on the dose and is approximately 6 hours when the drug is taken orally at a dose of 200 mg. Due to the non-linearity of pharmacokinetics, the terminal half-life does not allow predicting the accumulation or elimination of voriconazole.

Pharmacokinetics in special groups of patients with repeated oral use, Cmax and AUCt in healthy young women were 83% and 113% higher, respectively, than in young healthy men (18-45 years). There were no significant differences in Cmax and AUCt in healthy elderly men and healthy elderly women (>65 years).

There is no need to adjust the dose depending on gender. Plasma concentrations in men and women are similar.

Age at repeated oral use of Cmax and AUCt in healthy elderly men (>65 years) is 61% and 86% o, respectively, higher than in healthy young men (18-45 years). There were no significant differences in Cmax and AUCt in healthy elderly women (>65 years) and healthy young women (18-45 years). The safety of voriconazole in young and elderly patients is the same, and therefore no dose adjustment is required in the elderly.

Mean steady-state plasma concentrations of the drug in children receiving the drug at a dose of 4 mg/kg every 12 hours are comparable to those in adults receiving voriconazole at a dose of 3 mg / kg every 12 hours. The average concentration was 1186 ng / ml in children and 1155 ng / ml in adults. Therefore, the recommended maintenance dose in children aged 2 to

Dysfunction of poczeka single dose of voriconazole oral dose of 200 mg in patients with normal renal function and patients from mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance in patients with moderate or severe impairment of renal function (serum creatinine >220 µmol/l, or 2.5 mg/DL) was observed accumulation auxiliary substances included in the composition of the lyophilisate for preparation of solution for injection – SBECD.

Impaired liver function After a single oral dose (200 mg), the AUC of voriconazole in patients with mild or moderate cirrhosis of the liver (Child-Pugh A and B) is 233% higher than in patients with normal liver function. Impaired liver function does not affect the binding of voriconazole to plasma proteins.

With repeated oral use, the AUCX of voriconazole is comparable in patients with moderate cirrhosis of the liver (Child-Pugh B), who received the drug at a maintenance dose of 100 mg 2 times a day, and patients with normal liver function receiving voriconazole at a dose of 200 mg 2 times a day. There are no data on pharmacokinetics in patients with severe cirrhosis of the liver (Child-Pugh C).

Indications

-Invasive aspergillosis.

– Candidaemia in patients without neutropenia.

– Severe invasive candida infections (including C. krusei).

– Candidiasis of the esophagus.

– Severe fungal infections caused by Scedosporium spp. and Fusarium spp.

– Other severe invasive fungal infections when intolerant or refractory to other medications.

– Prevention of “breakthrough” fungal infections in patients with reduced immune system function, fever and neutropenia from high-risk groups (recipients of hematopoietic stem cell transplantation, patients with recurrent leukemia).

– Prevention of invasive fungal infections in high-risk patients (adults and children over 12 years of age), such as recipients of hematopoietic stem cell transplantation.

Use during pregnancy and lactation

There is no adequate information on the use of voriconazole in pregnant women.

Animal studies have shown that the drug in high doses has a toxic effect on reproductive function. The possible risk to humans is not known.

Voriconazole should not be used in pregnant women unless the expected benefit to the mother clearly outweighs the possible risk to the fetus.

The elimination of voriconazole in breast milk has not been studied. Voriconazole should not be used in breast-feeding women unless the expected benefit clearly outweighs the risk.

Contraindications

-Vifend® is contraindicated in patients with hypersensitivity to voriconazole or any other component of the drug.

– Concomitant use of Vifenda® and the following medications is contraindicated (seesection “Interaction with other medicinal products”): substrates of the CYP3A4 isoenzyme – terfenadine astemizole cisapride pimozide or quinidine; sirolimus; rifamiicin carbamazepine and long-acting barbiturates (phenobarbital); rifabutin; efavirenz in doses of 400 mg and above once a day (with voriconazole in standard doses); ritonavir in high doses (400 mg and above twice a day); alkaloids ergot (ergotamine dihydroergotamine), which are substrates of the CYP3A4 isoenzyme; St. John’s wort (inducer of cytochrome P 450 and P-glycoprotein).

– Vifend® is contraindicated in children under 2 years of age.

With caution:

– Hypersensitivity to other drugs-derivatives of azoles.

– Severe hepatic insufficiency severe renal insufficiency.

– Voriconazole should be used with caution in patients with proarrhythmic conditions: congenital or acquired prolongation of the QT interval cardiomyopathy, especially with heart failure sinus bradycardia the presence of symptomatic arrhythmia simultaneous use of drugs that cause prolongation of the QT interval (see the section “Special instructions”).

– Caution should also be exercised when using Vifend® in patients with electrolyte disorders such as: hypokalemia, angiomagnesemia and hypocalcemia.

Side effects

The most common adverse reactions are visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, and abdominal pain. Adverse reactions were usually mild to moderate.

Common: fever, peripheral edema (very common); chills, asthenia, chest pain, injection site reactions/inflammation, flu-like syndrome (common).

Cardiovascular system: low blood pressure, thrombophlebitis, phlebitis (common); atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmia, supraventricular tachycardia, QT prolongation, ventricular fibrillation (rare); complete atrioventricular block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter) (very rare).

Digestive system: nausea, vomiting, diarrhea, abdominal pain (very common); increased liver function (including ACT, ALT, alkaline phosphatase, gamma-HT, LDH, bilirubin), jaundice, cheilitis, gastroenteritis, cholestatic jaundice (common); cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue edema, peritonitis (rare); pseudomembranous colitis, hepatic coma (very rare).

Endocrine system: adrenal insufficiency (rare); hyperthyroidism, hypothyroidism (very rare). Immune system: allergic reactions, anaphylactoid reactions (rare).

Blood and lymphatic system: thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia (often); lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, suppression of bone marrow hematopoiesis (rarely); lymphangitis (very rarely).

Metabolism and nutrition: hypokalemia, hypoglycemia (often); hypercholesterolemia (rarely).

Musculoskeletal system: back pain (common); arthritis (rare).

The nervous system: headache (very common); dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia (common); Ataxia, cerebral edema, hypertension, hyposthesia, nystagmus, syncope (rare); Hyenne-Barre syndrome, oculomotor crisis, extrapyramidal syndrome, insomnia, encephalopathy, drowsiness during infusion (very rare).

Respiratory system: respiratory distress syndrome, pulmonary edema, sinusitis (common).

Skin and subcutaneous tissues: rash (very common); pruritus, maculopapular rash, photosensitivity skin reactions, alopecia, exfoliative dermatitis, facial edema, purpura (common); fixed drug rash, eczema, psoriasis, Stevens-Johnson syndrome, urticaria (rare); angioedema, discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis (very rare).

Sensory organs: visual disturbances (including impaired / enhanced visual perception, blurred vision, color vision changes, photophobia) (very common); blepharitis, optic neuritis, optic nipple edema, scleritis, impaired taste perception, diplopia (rare); retinal hemorrhage, corneal opacity, optic atrophy, hypoacusia, tinnitus (very rare).

Genitourinary system: increased creatinine, acute renal failure, hematuria (common); increased residual urea nitrogen, albuminuria, nephritis (rare); renal tubular necrosis (very rare).

Interaction

Voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes can cause, respectively, an increase or decrease in plasma concentrations of voriconazole.

When used concomitantly with rifampicin (a CYP P450 inducer) at a dose of 600 mg/day, the Cmax and AUC of voriconazole are reduced by 93% and 96%, respectively (this combination is contraindicated).

When co-administered with Vifend, ritonavir (a CYP P450 inducer, inhibitor, and CYP3A4 substrate) at a dose of 400 mg every 12 hours reduced the steady-state Cmax and oral AUC of voriconazole by an average of 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. Repeated oral use of voriconazole was found to have no significant effect on the steady-state Cmax and AUC of ritonavir, also taken repeatedly (concomitant use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).

When combined with powerful inducers of CYP P450 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. This combination is contraindicated.

When combined with cimetidine (a non-specific CYP P450 inhibitor) at a dose of 400 mg 2 times/day, the Cmax and AUC of voriconazole increase by 18% and 23%, respectively (no dose adjustment is required for Vifend).

Ranitidine at a dose of 150 mg 2 times / day when used together does not significantly affect the Cmax and AUC of voriconazole.

Erythromycin (a CYP3A4 inhibitor) when administered at a dose of 1 g 2 times/day and azithromycin at a dose of 500 mg 1 time/day do not significantly affect the Cmax and AUC of voriconazole.

Voriconazole inhibits the activity of cytochrome P450 isoenzymes-CYP2C19, CYP2C9, and CYP3A4, so it is possible to increase plasma concentrations of drugs that are metabolized by these isoenzymes.

Concomitant use of voriconazole with terfenadine, astemizole, cisapride, pimozide and quinidine may significantly increase their plasma concentrations, which may lead to prolongation of the QT interval and, in rare cases, to the development of ventricular fibrillation/flutter (this combination is contraindicated).

When used together, voriconazole increases the Cmax and AUC of sirolimus (2 mg once) by 556% and 1014%, respectively (this combination is contraindicated).

When used concomitantly, voriconazole may cause an increase in the concentration of ergot alkaloids (ergotamine and dihydroergotamine) in plasma and the development of ergotism (this combination is contraindicated).

When used together in patients who have undergone kidney transplantation and are in a stable condition, voriconazole increases the Cmax and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of developing nephrotoxic reactions. When prescribing voriconazole to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. After discontinuation of voriconazole, it is necessary to monitor cyclosporine levels and, if necessary, increase its dose.

When used together, voriconazole increases the Cmax and AUC of tacrolimus (used at a dose of 0.1 mg / kg once) by 117% and 221%, respectively, which may be accompanied by nephrotoxic reactions. When prescribing voriconazole to patients receiving tacrolimus, it is recommended to reduce the dose of the latter to 1/3 and monitor its plasma levels. After discontinuation of voriconazole, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.

Concomitant use of voriconazole (300 mg twice daily) and warfarin (30 mg once daily) was accompanied by an increase in the maximum prothrombin time to 93%. When warfarin and voriconazole are co-administered, it is recommended to monitor prothrombin time.

Voriconazole, when co-administered, may cause an increase in plasma concentrations of phenprocumone, acenocoumarol (substrates of CYP2C9, CYP3A4) and prothrombin time. If patients receiving coumarin preparations are prescribed voriconazole, it is necessary to monitor the prothrombin time at short intervals and adjust the dose of anticoagulants accordingly.

When used together, voriconazole can cause an increase in the concentration of sulfonylurea derivatives (CYP2C9 substrates) – tolbutamide, glipizide and glibenclamide in plasma and cause hypoglycemia. When they are used simultaneously, it is necessary to carefully monitor blood glucose levels.

In vitro, voriconazole inhibits the metabolism of lovastatin (a CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of statins metabolized by CYP3A4, which may increase the risk of rhabdomyolysis. When they are used simultaneously, it is recommended to evaluate the feasibility of adjusting the statin dose.

In vitro, voriconazole inhibits the metabolism of midazolam (a CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and develop a prolonged sedative effect. With the simultaneous use of these drugs, it is recommended to discuss the feasibility of adjusting the dose of benzodiazepine.

When used together, voriconazole may increase the content of periwinkle alkaloids (CYP3A4 substrates) – vincristine, vinblastine in plasma and lead to the development of neurotoxic reactions. It is recommended to discuss the feasibility of adjusting the dose of periwinkle alkaloids.

Voriconazole increases the Cmax and AUC of prednisone (a CYP3A4 substrate) administered at a single dose of 60 mg by 11% and 34%, respectively. No dose adjustment is recommended.

When used concomitantly, voriconazole does not significantly affect the Cmax and AUC of digoxin, administered at a dose of 0.25 mg 1 time / day.

When used together, voriconazole does not affect the Cmax and AUC of mycophenolic acid, prescribed at a dose of 1 g.

When administered concomitantly with Vifend, efavirenz (a CYP P450 inducer, inhibitor, and CYP3A4 substrate) administered at a dose of 400 mg once daily at steady state reduces the Cmax and AUC of voriconazole by an average of 61% and 77%, respectively. Voriconazole at steady state (400 mg orally every 12 hours on the first day, then 200 mg orally every 12 hours for 8 days) increases the steady-state Cmax and AUC of efavirenz by an average of 38% and 44%, respectively (this combination is contraindicated).

When co-administered, phenytoin (a CYP2C9 substrate and a potent cytochrome P450 inducer) administered at a dose of 300 mg 1 time/day reduces the Cmax and AUC of voriconazole by 49% and 69%, respectively; and voriconazole (400 mg 2 times/day) increases the Cmax and AUC of phenytoin by 67% and 81%, respectively (if necessary, co-use should carefully assess the ratio of the intended benefit and potential risk of combination therapy, as well as carefully monitor the levels of phenytoin in plasma).

Co-use of rifabutin (a cytochrome P450 inducer) administered at a dose of 300 mg 1 time/day reduces the Cmax and AUC of voriconazole (200 mg 1 time/day) by 69% and 78%, respectively. When combined with rifabutin, the Cmax and AUC of voriconazole (350 mg 2 times/day) is 96% and 68%, respectively, of the values for monotherapy with voriconazole (200 mg 2 times/day). When using voriconazole at a dose of 400 mg 2 times/day, Cmax and AUC are 104% and 87% higher, respectively, than when using voriconazole at a dose of 200 mg 2 times/day. Voriconazole 400 mg twice daily increases rifabutin Cmax and AUC by 195% and 331%, respectively. With simultaneous treatment with rifabutin and voriconazole, it is recommended to regularly conduct a detailed analysis of the peripheral blood picture and monitor the undesirable effects of rifabutin (for example, uveitis).

When co-administered at a dose of 40 mg 1 time/day, omeprazole (an inhibitor of CYP2C19; a substrate of CYP2C19 and CYP3A4) increases the Cmax and AUC of voriconazole by 15% and 41%, respectively, and voriconazole increases the Cmax and AUC of omeprazole by 116% and 280%, respectively (therefore, no dose adjustment of voriconazole is required, and the dose of omeprazole should be halved). The possibility of drug interaction of voriconazole with other H+-K+-ATPASE inhibitors, which are substrates of CYP2C19, should be considered.

Indinavir (a CYP3A4 inhibitor and substrate) administered at a dose of 800 mg 3 times / day does not significantly affect the Cmax and AUC of voriconazole, and voriconazole does not affect the Cmax and AUC of indinavir.

When used concomitantly with other HIV protease inhibitors (substrates and inhibitors of CYP3A4), the patient’s condition should be carefully monitored for possible toxic effects, since in vitro studies have shown that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) can mutually inhibit each other’s metabolism.

When voriconazole is co-administered with non – nucleoside reverse transcriptase inhibitors (CYP3A4 substrates, cytochrome P450 inhibitors or inducers), it should be taken into account that efavirenz and nevirapine can induce voriconazole metabolism, while delaverdine and efavirenz can inhibit it; voriconazole, in turn, can inhibit the metabolism of reverse transcriptase inhibitors. When voriconazole is co-administered with non-nucleoside reverse transcriptase inhibitors, patients should be monitored for possible toxic effects.

How to take, course of use and dosage

The drug Vifend® it is not recommended to enter in the form of bolus injections (jet). The infusion rate should not exceed 3 mg / kg / h for 1-3 hours.

Before starting therapy, it is necessary to correct such electrolyte disturbances as hypokalemia, hypomagnesemia and hypocalcemia (see the section “Side effects”).

Adult patients

use of Vifend® should begin with intravenous use at the recommended saturating dose in order to achieve adequate plasma concentrations on the first day. Intravenous use should be continued for at least 7 days after which it is possible to switch to oral use of the drug, provided that the patient is able to take medications for oral use. Given the high oral bioavailability of the drug reaching 96% (see section “Pharmacokinetics”), if there are clinical indications, you can switch from intravenous to oral use of the drug without dose adjustment.

The table shows detailed information on the dosage of the drug Vifend®:

Selection of the dose for intravenous use

If treatment is not effective enough, the maintenance dose of Vifend® for intravenous use can be increased to 4 mg/kg every 12 hours. If the patient does not tolerate the drug in a high dose, it is reduced to 3 mg/kg every 12 hours.

The duration of treatment should be as short as possible, depending on the clinical effect and the results of the mycological study. The duration of treatment should not exceed 180 days.

Prevention in adults and children

Prophylactic use of the drug should begin on the day of transplantation and can be continued for up to 100 days. Prevention can be extended up to 180 days after transplantation only if immunosuppressive therapy continues or a graft – versus-host reaction develops. The safety and efficacy of voriconazole when administered for more than 180 days have not been adequately studied in clinical trials. The dosage regimen for prevention is the same as for treatment in the appropriate age groups.

Impaired renal function

In patients with moderate or severe renal insufficiency (creatinine clearance In such patients, Vifend® should be administered orally unless the intended benefit of intravenous use outweighs the potential risk. In such situations, it is necessary to regularly monitor the concentration of creatinine and in case of its increase, the possibility of switching to oral voriconazole should be discussed.

Voriconazole is eliminated during hemodialysis with a clearance of 121 ml / min. A 4-hour hemodialysis session does not remove a significant part of the voriconazole dose and does not require its correction. Betadex sodium sulfobutylate is eliminated during hemodialysis with a clearance of 55 ml / min.

Impaired liver function

In acute liver damage with increased activity of “hepatic” transaminases: alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), dose adjustment is not required, but it is recommended to continue monitoring liver function indicators. Patients with mild or moderate hepatic impairment (Child-Pugh class A and B) should be given a standard saturating dose of Vifend® and the maintenance dose should be reduced by 2 times. In patients with severe hepatic impairment (Child-Pugh Class C), Vifend® should be prescribed only when the expected benefit exceeds the possible risk and under constant monitoring in order to detect signs of toxic effects of the drug.

Elderly patients

No dose adjustment is required in the elderly.

Use in children

The safety and efficacy of voriconazole in children under 2 years of age have not been established.

Dosage regimen of voriconazole in children (aged 2 to 12 years) and adolescents aged 12 to 14 years and weighing less than 50 kg:

Therapy is recommended to start with intravenous use of the drug and the possibility of oral use of Vifend® should be considered only after clinical improvement and the patient’s ability to take oral medications.

It should be taken into account that the effect of the drug when administered intravenously at a dose of 8 mg / kg is approximately twice as high as when administered orally at a dose of 9 mg/kg. The use of voriconazole in children aged 2 to 12 years with impaired liver or kidney function has not been studied.

In adolescents (aged 12 to 14 years with a body weight of 50 kg or more; from 15 to 18 years, regardless of body weight), voriconazole is dosed in the same way as for adults.

Dose adjustment

If the patient’s clinical response is inadequate, the dose can be increased in increments of 1 mg/kg (or 50 mg if the maximum oral dose of 350 mg was initially used). If the child does not tolerate treatment, you can reduce the dose of voriconazole in increments of 1 mg / ml (or 50 mg if the maximum oral dose of 350 mg was initially used).

Instructions for preparing a solution for infusions

Vifend® is available in single-dose vials. The contents of the vial are reconstituted by dissolving in 19 ml of water for injection and 20 ml of a clear concentrate containing voriconazole at a concentration of 10 mg/ml is obtained. If the solvent does not enter the bottle under the influence of vacuum, then the bottle can not be used. Before use, the required volume of concentrate (see table) is added to the recommended compatible infusion solution (see below) and a solution containing voriconazole is obtained in concentrations from 05 mg / ml to 5 mg / ml.

Required volumes of Vifend ® concentrate 10 mg / ml:

Vifend ® Lyophilizate for infusion solution preparation is a sterile, preservative-free lyophilizate intended for single use. From a microbiological point of view, the drug should be administered immediately. The reconstituted solution (concentrate) can be stored for no more than 24 hours at a temperature of 2 to 8 °C if it was prepared under controlled aseptic conditions.

The concentrate can be further diluted with the following solutions:

– 09% solution of sodium chloride for intravenous injection;

solution of ringer’s lactate for intravenous injection;

5% dextrose and normal saline and ringer’s lactate for intravenous injection;

5% dextrose solution and 045% solution of sodium chloride for intravenous injection;

5% dextrose solution for intravenous injection;

5% dextrose solution and 015% solution of potassium chloride for intravenous use;

– 045% solution of sodium chloride for intravenous injection;

5% dextrose solution and 09% a solution of sodium chloride for intravenous injection.

Compatibility of voriconazole with other solutions other than those indicated above is unknown.

Overdose

Three cases of accidental overdose are known. All of these cases occurred in children who received an intravenous dose of voriconazole five times higher than the recommended dose. A single case of photophobia lasting 10 minutes has been reported. The antidote of voriconazole is unknown. In case of overdose, symptomatic and supportive therapy is indicated. Voriconazole is eliminated during hemodialysis with a clearance of 121 ml / min. betadex sodium sulfobutylate-with a clearance of 55 ml / min. 13 in case of overdose, hemodialysis may help to remove voriconazole and betadex sodium sulfobutylate from the body.

Special instructions

Sampling for culture and other laboratory tests (serology, histopathology) in order to isolate and identify pathogens should be carried out before starting treatment. Therapy can be initiated before receiving the results of culture and other laboratory tests, but if they are available, treatment should be adjusted accordingly. Clinical strains with reduced sensitivity to voriconazole were identified.

However, elevated minimum inhibitory concentrations (MPC) do not always predict clinical ineffectiveness; voriconazole has been shown to be effective in patients infected with 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 borderline concentrations of voriconazole that allow us to assess sensitivity to this drug have not been established. Hypersensitivity: Patients with hypersensitivity to other azoles should be prescribed voriconazole with caution

Adverse events from the cardiovascular system: the use of voriconazole is associated with prolongation of the QT interval on the electrocardiogram, which is accompanied by rare cases of ventricular fibrillation-flutter in patients receiving voriconazole therapy (in seriously ill patients with multiple risk factors, such as cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of this complication). In patients with these potentially proarrhythmic conditions, voriconazole should be administered with caution (see section Dosage and use). Hepatotoxicity: When treated with voriconazole, there are infrequent (0.1-1%%) cases of serious liver reactions (including clinically manifested hepatitis, cholestasis and hepatic cell failure, including with a fatal outcome). Adverse events from the liver are mainly observed in patients with serious diseases (mainly malignant blood tumors). Patients without any risk factors have transient liver reactions, including hepatitis and jaundice. Liver function disorders are usually reversible and resolve after discontinuation of treatment.

Monitoring of liver function: During treatment with voriconazole, it is recommended to regularly monitor liver function, especially liver tests and bilirubin. If there are clinical signs of liver disease that may be associated with voriconazole, it is necessary to discuss the feasibility of discontinuing therapy. Adverse events from the kidneys: Severe patients receiving voriconazole have cases of acute renal failure.

Monitoring of renal function:Patients should be monitored for signs of impaired renal function. To do this, it is necessary to conduct laboratory tests, in particular to determine the serum creatinine level. Infusion reactions: When voriconazole is administered intravenously, infusion reactions are observed, mainly “flushes of blood to the face” and nausea. If these symptoms are severe, the advisability of discontinuing treatment should be discussed (see section Side effects). Skin reactions: In rare cases, patients treated with voriconazole develop exfoliative skin reactions, such as Stevens-Johnson syndrome. When a rash appears, patients should be monitored. With the progression of skin lesions, voriconazole should be discontinued. In addition, the use of voriconazole was accompanied by skin reactions of photosensitivity, especially during long-term treatment. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight.

Cyclosporine and tacrolimus (CYP3A4 substrates): Patients receiving cyclosporine or tacrolimus may experience clinically significant interactions with voriconazole (see section Interactions with other drugs and other forms of interaction). Phenytoin (CYP2C9 substrate and potent CYP450 inducer): When phenytoin is co-administered with voriconazole, continuous monitoring of phenytoin levels is recommended. If possible, the concomitant use of voriconazole and phenytoin should be avoided unless the expected benefit outweighs the possible risk (see section Interactions with other drugs and other forms of interaction).

Rifabutin (CYP450 inducer): When rifabutin is co-administered with voriconazole, it is recommended to conduct a clinical blood test and monitor for undesirable effects of rifabutin (for example, uveitis). Concomitant use of voriconazole and rifabutin should be avoided unless the expected benefit outweighs the possible risk (see section Interactions with other drugs and other forms of interaction). Women of reproductive agewomen of reproductive age should always use effective methods of contraception during treatment.

Effects on the ability to drive and use Technicoloriconazole may cause transient and reversible visual disturbances, including blurred vision, impaired / enhanced visual perception, and / or photophobia. If these symptoms are present, patients should avoid performing potentially dangerous activities such as driving a car or using complex machinery. When taking voriconazole, patients should not drive at night.

Form of production

Lyophilizate for preparation of solution for infusions.

Storage conditions

Lyophilizate for preparation of infusion solution: at a temperature not exceeding 30°C. Dissolved concentrate: at a temperature from 2°C to 8°C.

Shelf

life is 2 years. Reconstituted solution – no more than 24 hours.

Active ingredient

Voriconazole

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

Adult Doctor’s prescription