VYFEND (Pills)

Active material: voriconazole
When ATH: J02AC03
CCF: Antifungal antibiotic
ICD-10 codes (testimony): B37.1, B37.6, B37.7, B37.8, B44, B48.2, B48.7, Z29.8
When CSF: 08.01.01
Manufacturer: HEINRICH MACK NEXT. GmbH & Co. KG (Germany)

Pharmaceutical form, composition and packaging

Pills, coated white or nearly white, round, lenticular, Engraved “Pfizer” on one side and “VOR50” – another.

Excipients: lactose monohydrate, pre-gelatinized starch, sodium croscarmellose, povidone, magnesium stearate.

The composition of the shell: Opadry White OY-LS-28914 (gipromelloza, Titanium dioxide, lactose monohydrate, glycerol triacetate).

2 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (5) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pills, coated white or nearly white, oblong, lenticular, Engraved “Pfizer” on one side and “VOR200” – another.

Excipients: lactose monohydrate, pre-gelatinized starch, sodium croscarmellose, povidone, magnesium stearate.

The composition of the shell: Opadry White OY-LS-28914 (gipromelloza, Titanium dioxide, lactose monohydrate, glycerol triacetate).

2 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (5) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pharmacological action

Broad-spectrum antifungal medication from the Group of triazoles. The mechanism of action associated with inhibition of demethylation 14α-sterola, mediated fungal cytochrome P450, This reaction is a key step in the biosynthesis of ergosterol.

In vitro voriconazole has a broad spectrum antifungal action, active against Candida spp. (including strains of Candida krusei, resistant to fluconazole, and resistant strains of Candida glabrata and Candida albicans) and has antifungal effect against all the strains of Aspergillus spp., as well as pathogenic fungi, become relevant in recent times, including Fusarium or Scedosporium, which, to a limited extent, susceptible to antifungal means.

Clinical efficacy of vorikonazola has been demonstrated when infections, caused by Aspergillus spp. (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Aspergillus nidulans), Candida spp. (including strains of Candida albicans, Candida of Dublin, Candida glabrata, White invisible, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida guillermondii), Scedosporium spp. (Scedosporium apiospermum injection including/Pseudoallescheria boydii/, Scedosporium prolifecans) and Fusarium spp..

Other fungal infections, where Cypermethrin (often with a partial or complete response), include individual cases of infections, caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Merciless Coccidoides, The genus conidiobolus coronatus, Cryptococcus neoformans, Exserohilus rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, From paecilomyces lilacinus, Penicillium spp.. (including Penicillium marneffei), Philaphora richardsiae, Scopulariopsis brevicaulis and Trychosporon spp. (including Trychosporon beigelii).

In vitro demonstrated activity of vorikonazola against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains had been kept at concentrations of vorikonazola 0.05 to 2 ug / ml.

In vitro vorikonazola activity detected against Curvularia spp.. and Sporothrix spp., However, the clinical significance of its unknown.

Pharmacokinetics

Pharmacokinetic parameters vorikonazola are characterized by considerable mežindividual′noj variability.

Absorption and distribution

Pharmacokinetics vorikonazola is a non-linear saturation at the expense of its metabolism. If the dose is observed a disproportionate (more pronounced) increase in AUC. Increasing the oral dose 200 mg 2 times / day to 300 mg 2 times / day results in an increase in average AUC 2.5 times. The on / in the introduction or ingestion bolus plasma concentration approaching equilibrium during the first 24 no. If the drug is prescribed 2 times per day in average (not in drums) doses, the accumulation of the drug, and equilibrium concentrations are achieved by the 6th day in most patients.

Voriconazole is rapidly and almost completely absorbed after oral administration; C_max plasma levels achieved after 1-2 h after administration. Bioavailability of voriconazole when administered is 96%, Repeated dose with food rich in fats C_max and AUC are reduced by 34% and 24% respectively. Suction voriconazole is independent of the pH of gastric juice.

The Calculated V_d vorikonazola in equilibrium is 4.6 l / kg, that points to the active drug distribution in tissue. Binding to plasma proteins is 58%.

Voriconazole permeates through GEB and defined in cerebrospinal fluid.

Metabolism and excretion

According to in vitro studies found, Voriconazole is metabolised by the action of hepatic isozymes CYP2C19, CYP2C9, CYP3A4, When the 2s19 plays an important role in the metabolism of vorikonazola. This enzyme exhibits a pronounced genetic polymorphism, Therefore it is possible to vorikonazola metabolism at cnižennyj 15-20% patients of Asian descent and 3-5% Caucasian patients and blacks. Studies from representatives of the European race and the Japanese have shown, patients with reduced metabolism AUC vorikonazola for an average of 4 times higher, than the homozygous patients with high metabolism. From heterozygous patients with active metabolism AUC vorikonazola on average in 2 times higher, than the homozygous.

The main metabolite is N-vorikonazola oxide (72% among plasma circulating metabolites, labeled with a radioactive label). This metabolite has minimal antifungal activity.

In an unmodified form with urine output less than 2% from imposed dosage.

After repeated ingestion or on / in the urine is detected in approximately 83% and 80% dose radiolabeled respectively. Most of (>94%) the total dose is excreted within the first 96 hours after ingestion and on / in the.

T_1/2 in the terminal phase of voriconazole is dependent on the dose and is approximately 6 h while taking the drug orally at a dose 200 mg. In connection with non-linear pharmacokinetics value of T_1/2 does not allow to predict cumulation or excretion of vorikonazola.

Pharmacokinetics in special clinical situations

Gender and age. Repeated dose drug inside C_max and AUC were healthy young women 83% and 113% correspondingly higher, than in healthy young males (18-45 years). No significant differences C_max and AUC in healthy elderly males and healthy elderly women (≥ 65 years) no.

The need for dose adjustment depending on the floor not indicated. plasma concentrations in males and females are similar.

Repeated dose drug inside C_max and AUC in healthy older men (≥ 65 years) on 61% and 86% correspondingly higher, than in healthy young males (18-45 years). No significant differences C_max and AUC in healthy older women (≥ 65 years) and healthy young women (18-45 years) no.

Safety vorikonazola in young and elderly patients the same, therefore a need for dose adjustment in use in elderly patients is not required.

Middle C_ss the drug in the blood plasma of children, receiving a drug dose 4 mg / kg every 12 no, comparable to those in adults, receiving a dose of voriconazole 3 mg / kg every 12 no. The average concentration was 1186 ng / ml in children and 1155 ng / mL in adults. In this regard, the recommended maintenance dose in children aged 2 to 12 s is 4 mg / kg every 12 no.

Impaired renal function. In single dose of the drug orally at a dose 200 mg in patients with normal renal function and patients of lung (CC 41-60 ml / min) to heavy (CC less than 20 ml / min) renal dysfunction pharmacokinetics of voriconazole is not significantly dependent on the degree of violation. Binding to plasma proteins is similar in patients with various degrees of renal insufficiency.

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

Repeated dose drug inside voriconazole AUC is comparable in patients with moderate hepatic cirrhosis (Class B for Child-Pugh), receiving the drug at a maintenance dose 100 mg 2 times / day, and in patients with normal liver function, receiving a dose of voriconazole 200 mg 2 times / day. Information about the pharmacokinetics vorikonazola in patients with severe hepatic cirrhosis (class C Child-Pugh) no.

Testimony

-invasive aspergillosis;

— severe Candidal infections invasive form (including Candida krusei);

-Esophageal Candidosis;

— severe fungal infections, caused by Scedosporium spp. and Fusarium spp.;

— severe fungal infections with intolerance or previously to other medicines;

— Prevention breakthrough fungal infections in patients with fever from high-risk groups (recipients of bone marrow allogennogo, patients with recurrent leukemia).

Dosage regimen

The drug is taken orally for 1 h or through 1 hours after meals.

Adults Vfend^® appointed interior in the first day at the recommended dose of saturating, to the first day of therapy to achieve vorikonazola concentration in the blood plasma is close to equilibrium.

Given the high bioavailability when administered (96%), If there is clinical evidence can transition from parenteral to oral.

Titration

In case of insufficient effectiveness of the therapy maintenance dose for oral administration may be increased up to 300 mg every 12 no, and in patients with a body weight up to 40 kg dose can be increased to 150 mg every 12 no.

When intolerance of the drug in this higher dose on its lower 50 mg to achieve a dose of 200 mg every 12 h inside (or 100 mg every 12 h for patients weighing less 40 kg).

In an application with a maintenance dose of phenytoin Vfend^® for oral administration to increase the 200 to 400 mg every 12 no (with 100 mg 200 mg every 12 hours in patients weighing less 40 kg).

In an application with a maintenance dose of rifabutin Vfend^® for oral administration to increase the 200 to 350 mg every 12 no (with 100 mg 200 mg every 12 hours in patients weighing less 40 kg).

Length of therapy depends on the clinical effect and results of mikologičeskogo studies.

Correction dosing regimen in elderly patients not required.

There is no need to correct dosing regimen Vfend^® for oral administration in patients with impaired renal function.

Voriconazole displays gemodialise with ground 121 ml / min, 4-hour hemodialysis session does not remove significant portion of the vorikonazola and does not require dose adjustment. SBECD appears during hemodialysis with ground 55 ml / min.

At acute liver damage with increased activity transaminaz (GOLD, IS) correction dose not required, but should monitor the status of the liver with a view to identifying further increase transaminaz.

Patients with cirrhosis of mild or moderate severity (class a and b on a scale Child-Pugh) recommend appoint Vfend^® in the standard shock dose, a dose decrease in 2 times.

Patients with severe hepatic impairment Vfend^® You can assign only in cases, the projected benefits exceed the potential risk, in this case, you must constantly monitor the patient in order to identify drug toxicity.

Experience in application of Vfend^® in children limited, that complicates the choice of optimum dosage. A breakdown of the drug in children aged 2 to 12 years, used in pharmacokinetic studies, are presented in Table.

If possible ingestion of the drug, the dose is rounded to the nearest multiple of 50 mg, and administered as whole tablets. Portability of the higher doses in children has not been studied.

To children aged 12 years before 16 years the dosage of the drug is the same, for adults.

Side effect

The most common adverse reactions: visual impairment, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abdominal pain. Adverse reactions were usually easy or moderately expressed. Clinically meaningful drug security dependencies from the age, race or gender is not revealed.

Below are the unwanted reactions, observed in the application of the drug and, probably, associated with the therapy..

Criteria for evaluating the frequency of adverse reactions: Often – ≥10%; often – by ≥1% to <10%; seldom-of ≥ 0.1% to <1%; very rarely-from 0.01% to <0.1%.

From the body as a whole: very often-fever, peripheral edema; often-shivers, asthenia, chest pain, reaction and inflammation at the injection site, flu-like symptoms.

Cardio-vascular system: often, a decline ad, tromboflebit, phlebitis; rare-predserdnye arrhythmias, bradycardia, tachycardia, ventricular arrhythmias, QT prolongation, ventricular fibrillation; very rarely-ventricular tachycardia (including ventricular fibrillation), complete AV-block, bundle branch block, nodal arrhythmia.

From the digestive system: very often - nausea, vomiting, diarrhea, stomach ache; often increased activity ALT, IS, Alkaline phosphatase, LDH, GGT and cium in plasma, jaundice, cheilitis, gastroenteritis, cholestasis; seldom-cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, enlargement of the liver, gingivitis, glossitis, hepatitis, hepatic failure, pancreatitis, swelling of the tongue, peritonitis; very rarely-pseudomembranous colitis, pechenochnaya coma. The overall frequency of clinically significant increase in transaminaz is 13.4%. The liver may be associated with higher concentrations in plasma or doses of the drug, and in most cases disappear with continued therapy (without changing the dose, or after the correction) or when its abolition. In patients with severe major diseases (malignant hematologic diseases) against the backdrop of vorikonazola rare cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular insufficiency, leading to death).

On the part of the endocrine system: seldom-adrenal insufficiency; very rarely-hyperthyroidism, gipotireoz.

Allergic reactions: rarely – Allergic and anaphylactoid reactions, toxic epidermal necrolysis, Stevens-Johnson syndrome, hives; very rarely-angioneurotic edema, discoid lupus erythematosus, erythema multiforme.

From the hematopoietic system: often thrombocytopenia, anemia (incl. macrocytic, microcitarnaya, normocytic, megaloblastnaya, aplastic), leukopenia, pancytopenia; seldom-Lymphadenopathy, agranulocytosis, eozinofilija, disseminated intravascular coagulation syndrome, suppression of bone marrow hematopoiesis; very rarely-Lymphangitis.

Metabolism: often-hypokalemia, gipoglikemiâ; rare-gipoholesterinemia.

On the part of the musculoskeletal system: often – backache; seldom-arthritis.

From the central and peripheral nervous system: very often - headache; often - dizziness, hallucinations, confusion, depression, alarm, tremor, ažitaciâ, paresthesia; are rarely - ataxia, cephaledema, intracranial hypertension, gipesteziya, nistagmo, fainting; very rarely-Gijenna-Barre syndrome, okulomotornыy crisis, extrapyramidal syndrome, insomnia, encephalopathy, drowsiness during infusion.

The respiratory system: often respiratory distress syndrome, pulmonary edema, sinusitis.

Dermatological reactions: very often the rash; often-itchy, maculo-papular rash, photosensitivity, alopecia, exfoliative dermatitis, swelling of the face, purpura; rarely is eczema, psoriasis. Dermatological reactions in most cases easy or moderately expressed. However, with the appearance of a rash the patient should be carefully observed, and with the progression of skin changes drug should be lifted. Photosensitivity develops with prolonged use of the drug.

From the senses: often – visual impairment (including violation of/enhancement of visual perception, mist, changing color perception, photophobia); seldom-blepharitis, optic neuritis, papilledema, scleritis, violation of taste perception, diplopia; very rarely-bleeding in the retina, aglia, optic atrophy, gipoakuziя, tinnitus. Visual impairment is often observed (approximately 30% blurred vision, changes in color vision, photophobia), in most cases, are transitory and fully reversible, disappear spontaneously within 60 m, easily expressed, rarely require discontinuation of treatment and do not lead to any consequences in the long term. In reconsidering the application indicated the weakening of their symptoms. Development mechanism not known, It is assumed the direct impact of the vorikonazola on the retina, as evidenced by the reduction in the amplitude of waves on èlektroretinogramme when examining the influence of vorikonazola on the retina in healthy volunteers. These changes are not rose with continued therapy for 29 days and completely disappeared after the abolition of voriconazole. The effect of a longer (more 29 days) the use of the drug on Visual function is not installed.

From the urinary system: often, increased creatinine in the serum, acute renal failure, hematuria; rarely-increasing residual urea nitrogen, albuminuria, jade; very rarely-renal tubular necrosis.

Contraindications

-simultaneous intake of medicines-CYP3A4 substrates-terfenadina, astemizola, cisapride, pimozida and hinidina;

-simultaneous reception sirolimusa;

-simultaneous intake of rifampicin, carbamazepine and long-acting barbiturates;

-simultaneous reception with ritonavir;

-simultaneous reception èfavirenzom;

-simultaneous reception with ergot alkaloids (ergotamine, digidroergotaminom);

- Hypersensitivity to the drug.

FROM caution prescribe the drug in patients with severe hepatic insufficiency, if you are hypersensitive to other drugs - derivatives of azoles. Safety and efficacy in children under 2 years have not been established.

Pregnancy and lactation

Adequate information on the safety of drugs in pregnancy is not. Vfend^® It should not be used in pregnancy, except, the expected benefit to the mother outweighs the potential risk to the fetus.

IN experimental studies Animal found, that voriconazole in high doses has toxic effects on the reproductive function. The potential risk for humans is not known.

Vorikonazola excretion in breast milk was not investigated. The drug should not be appointed during lactation (breast-feeding), except, when expected benefit exceeds the risk.

Women of reproductive age must use reliable methods of contraception during therapy Vifendom^®.

Cautions

Before therapy, you must adjust the electrolyte disorders such as hypokalemia, hypomagnesemia and hypocalcemia.

Sampling for cultural and other laboratory studies (serological, histopathologic) in order to highlight and identify pathogens should be performed before treatment. Therapy can start pending the results of laboratory research, and then, if necessary, adjust. Highlighted clinical strains, possessing a reduced sensitivity to vorikonazolu. However, elevated the IPC is not always possible to predict clinical inefficiency: There are cases, When voriconazole was effective in infections, caused by microorganisms, resistant to other azolam. To assess the correlation between activity in vitro and clinical results of the treatment of difficult, given the complexity of patients, which included in clinical research; the value of the border vorikonazola concentrations, to assess the sensitivity to this drug, not set.

Unwanted reactions on the part of the cardiovascular system

Application of vorikonazola can lead to longer QT interval on the ECG, accompanied by rare cases of flicker-atrial fibrillation in patients with multiple risk factors (kardiotoksičeskaâ chemotherapy, cardiomyopathy, gipokaliemia and concomitant therapy, that could contribute to the development of adverse events with the circulatory system). Patients with these potentially proarrhythmic conditions voriconazole should be administered with caution.

Gepatotoksichnostь

Unwanted effects from the liver, observed in the treatment of vorikonazolom, mainly appearing in patients with serious diseases (mostly malignant tumours of blood). In patients with no risk factors observed transient response from the liver, including hepatitis and jaundice. The liver is usually reversible and disappear after discontinuation of treatment. During treatment vorikonazolom should regularly monitor liver function (including liver function tests and the levels of bilirubin). With the appearance of clinical signs of liver disease, you should discuss whether the cessation of therapy.

Unwanted reactions on the part of the kidney

Patients have, treated with voriconazole and other nefrotoksicskie drugs and having co-morbidities, observed cases of acute renal failure. During the period of use of the drug should be monitored renal function (incl. the level of creatinine in the serum).

Dermatological reactions

With the progression of dermatological reactions drug should be lifted. Patients, applying Vfend^®, should avoid exposure to sunlight and UV radiation.

Phenytoin

If necessary, use Vifenda^® and fenitoina should carefully assess the expected benefit and the potential risk from the combination therapy and constantly monitor the fenitoina concentration in the blood plasma.

Rifabutin

If necessary, use Vifenda^® and rifabutin should carefully assess the expected benefit and the potential risk from the combination therapy and hold her under control picture peripheral blood, as well as other possible unwanted effects of rifabutin.

Use in Pediatrics

Safety and efficacy of Vifenda^® in children under 2 years not set.

Effects on ability to drive vehicles and management mechanisms

Because the drug can cause temporary visual impairment, including the mist before my eyes, violation/enhancement of visual perception and/or photophobia, then when you see such reactions, patients should not engage in potentially hazardous activities, such as, eg, driving a car or using complex technology. Against the backdrop of Vifenda^® patients should not drive the car in the dark.

Overdose

Treatment: the antidote is not known, if necessary, symptomatic therapy, gastric lavage may be. Voriconazole displays gemodialise with ground 121 ml / min. In case of overdose shows a kidney dialysis.

Drug Interactions

Voriconazole is metabolized under the effect of CYP2C19 Isoenzymes, CYP2C9 и CYP3A4. Inhibitors or inducers of these isoenzymes may cause increase or decrease respectively, concentrations in plasma vorikonazola.

Combinations, where there has been a significant decrease in the concentration of plasma vorikonazola

In an application with rifampicin (inducer of CYP450) dose 600 mg / C_max and AUC by vorikonazola 93% and 96% respectively (This combination is contraindicated).

Ritonavir (inducer of CYP450, the inhibitor and substrate of CYP3A4) dose 400 mg every 12 h reduced C_max in equilibrium and AUC of voriconazole, ingestable, on average 66% and 82% respectively. Influence of ritonavir at lower doses of voriconazole concentration is not yet known. Established, that repeated use of voriconazole inside has expressed no effect on the C_max in equilibrium and AUC of ritonavir, also received again (simultaneous application of voriconazole and ritonavir at a dose of 400 mg every 12 h contraindicated).

When coupled with the use of powerful inducers of CYP450 carbamazepine or long-acting barbiturates (fenoʙarʙitalom) possibly significant decrease in C_max vorikonazola plasma, Although their interaction was not investigated (Such combinations are contraindicated).

Combinations, which do not require dose adjustment vorikonazola

When coupled with the use of cimetidine (nonspecific inhibitor of CYP450) dose 400 mg 2 times / day C_max and AUC increased by vorikonazola 18% and 23% respectively.

Ranitidine dose 150 mg 2 times per day when there is a significant impact on C_max and AUC vorikonazola.

Erythromycin (CYP3A4 inhibitor) at an application rate 1 g 2 times/day and dose of azithromycin 500 mg 1 times/day do not have a significant impact on C_max and AUC vorikonazola.

Voriconazole inhibits the activity of CYP2C19 Isoenzymes, CYP2C9, CYP3A4, so may increase plasma concentrations of medicines, which are metabolized by these izofermentami.

Combinations contraindicated

If you are applying to vorikonazola with terfenadine, astemizolom, cizapridom, pimozidom and hinidine possible significant increase in their concentration in the plasma, that could lead to longer QT interval and in rare cases to develop flicker/atrial fibrillation.

When voriconazole improves C_max and AUC sirolimusa (2 mg dose) on 556% and 1014% respectively.

While applying voriconazole may cause increased concentrations of alkaloids lpv (ergotamine and dihydroergotamine) in the plasma and the development of ergotism.

Combinations, in the application that require permanent clinical supervision and correction doses of drugs

In a joint application in patients, undergoing a kidney transplant and are in stable condition, voriconazole improves C_max and AUC of Cyclosporine, at least, on 13% and 70% respectively, that has been accompanied by increased risk of nefrotoksicskih reactions. In the appointment vorikonazola patients, receiving cyclosporine, It is recommended to reduce the dose of Cyclosporine by half and control its concentration in blood plasma. After the abolition of vorikonazola need to control the concentration of Cyclosporine and, if necessary, increase the dose.

When voriconazole improves C_max and AUC Tacrolimus (used in dose 0.1 mg / kg once) on 117% and 221% respectively, that could be accompanied by nefrotoksičeskimi reactions. In the appointment vorikonazola patients, Receiving Tacrolimus, It is recommended to reduce the dose of the latter to 1/3 and control its levels in plasma. After the abolition of vorikonazola need to control the concentration of Tacrolimus and, if necessary, increase the dose.

Simultaneous application vorikonazola (dose 300 mg 2 times / day) and warfarin (30 mg 1 time / day) accompanied by an increase in the maximum protrombinovogo time to 93%. Together with the appointment of warfarin and vorikonazola to monitor prothrombin time.

Voriconazole in joint application may cause increased plasma concentrations of fenprokumona, atsenokumarola (CYP2C9 substrates, CYP3A4) and increased prothrombin time. If sick, receiving the coumarin drugs, appoint voriconazole, There is a need to monitor prothrombin time with short intervals and appropriately select doses of anticoagulants.

When voriconazole may cause increased concentrations derived sulfonylureas (CYP2C9 substrates) – tolʙutamida, glipizide and gliburida in plasma and cause hypoglycemia. While their application, it is necessary to carefully monitor blood glucose levels.

In vitro voriconazole inhibits metabolism lovastatina (a CYP3A4 substrate). In a joint application may increase the plasma concentration of Statins, metaboliziruthan under the influence of CYP3A4, that can increase the risk of rabdomioliza. While their application is recommended to assess the feasibility of dose adjustment statina. Increasing the concentration of statin drugs in the blood plasma is sometimes accompanied by the development of rhabdomyolysis.

In vitro voriconazole inhibits metabolism of Midazolam (a CYP3A4 substrate). When sharing application may increase the plasma concentration of CYP3A4 metabolized by the action of benzodiazepines (midazolama, triazolama, alprazolam) and development of prolonged sedation. In case of simultaneous use of these drugs is recommended to discuss the appropriateness of benzodiazepine dose adjustment.

In a joint application can increase the content of voriconazole vinca alkaloids (CYP3A4 substrates) – vinchristina, Vinblastine in the plasma and lead to the development of neirotoksicskih reactions. It is recommended that you discuss the usefulness of dose adjustment vinca alkaloids.

Combinations, in the application that do not require correction doses of drugs

Voriconazole improves C_max and AUC of prednisone (a CYP3A4 substrate), used in dose 60 mg dose, on 11% and 34% respectively.

While applying voriconazole has no significant effect on C_max and AUC of Digoxin, assigned dose 0.25 mg 1 time / day.

When voriconazole has no effect on C_max and AUC of mikofenolovoj acid, apply the dose 1 g.

Two-way communication

Together with the application Vifendom^® efavirenz (inducer of CYP450, the inhibitor and substrate of CYP3A4), used in the dose 400 mg 1 times/day equilibrium reduces C_max and AUC vorikonazola on average 61% and 77% respectively. Voriconazole in equilibrium (400 mg inside every 12 h on the first day, then 200 mg inside every 12 h for 8 days) increases the equilibrium (C)_max and AUC èfavirenza on average 38% and 44% respectively (dannaya combination contraindicated).

When the joint application of phenytoin (substrate CYP2S9 and powerful inducer of CYP450), used in the dose 300 mg 1 time / day, lowers C_max and AUC vorikonazola for 49% and 69% respectively; and voriconazole (400 mg 2 times / day) increases C_max and AUC fenitoina on 67% and 81% respectively (If necessary, joint application should carefully weigh the anticipated benefits and potential risks of combination therapy, as well as carefully monitored fenitoina concentration in the blood plasma).

When rifabutin (inducer of CYP450), used in the dose 300 mg 1 times/day reduces C_max and AUC vorikonazola (200 mg 1 time / day) on 69% and 78% respectively. When coupled with the use of rifabutinom (C)_max and AUC vorikonazola (350 mg 2 times / day) is accordingly 96% and 68% from figures alone vorikonazolom (200 mg 2 times / day). In applying vorikonazola in dose 400 mg 2 times/day_max and AUC, respectively, at 104% and 87% higher, than with monotherapy dose vorikonazolom 200 mg 2 times / day. Voriconazole in dose 400 mg 2 times per day increases (C)_max and AUC rifabutin at 195% and 331% respectively. While treatment rifabutinom and vorikonazolom it is recommended to regularly carry out a detailed analysis of the picture peripheral blood and control unwanted effects of rifabutin (eg, uveitis).

When dose 40 mg 1 times/day omeprazole (CYP2C19 inhibitor; substrate CYP2C19 and CYP3A4) increases C_max and AUC vorikonazola for 15% and 41% respectively, While voriconazole improves C_max and AUC of omeprazole on 116% and 280% respectively (Consequently, dose adjustment is not required vorikonazola, a dose of omeprazole should be reduced by half). You should consider the possibility of drug interaction vorikonazola with other inhibitors of h⁺-K⁺-ATPase, who are CYP2C19 substrates.

Indinavir (the inhibitor and substrate of CYP3A4), used in the dose 800 mg 3 times per day does not significantly affect the value of C_max and AUC vorikonazola, While voriconazole has no effect on C_max and AUC of indinavir.

Together with other HIV protease inhibitors (substrates and inhibitors of CYP3A4) the patient should be carefully monitored with a view to possible toxic effects, tk. in vitro studies have shown, that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, Nelfinavir) can mutually inhibit each other's metabolism.

When coupled with vorikonazola non nucleoside reverse transcriptase inhibitors (CYP3A4 substrates, inhibitors or inducers of CYP450) should be considered, that delaverdin can inhibit the metabolism of vorikonazola. Nevirapine may induce metabolism of voriconazole, Although this effect is not understood. Voriconazole, in turn, can inhibit the metabolism of reverse transcriptase inhibitors. If you are applying to vorikonazola with reverse transcriptase inhibitors non patients should be observed in order to identify possible toxic effects.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 3 year.