Вифенд®

General characteristics. Structure:

International unlicensed name: вориконазол
Active agent: вориконазол - 50 mg or 200 mg;
Excipients: lactoses monohydrate of 62,50 mg / 250,00 mg, starch of prezhelatinizirovanny 21,00 mg / 84,00 mg, croscarmellose sodium of 7,50 mg / 30,00 mg, povidone of 7,50 mg / 30,00 mg, magnesium stearate of 1,50 mg / 6,00 mg; film cover: опадрай white OY-LS-28914 (gipromelloza, titanium dioxide, lactoses monohydrate, triacetin) 3,75 mg / 15,00 mg.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Vorikonazol - antifungal drug of a broad spectrum of activity from group of triazoles. The mechanism of action of a vorikonazol is connected with demethylation inhibition 14α-стерола, mediated by fungal P450 cytochrome - a key stage of biosynthesis of ergosterol.

In vitro вориконазол possesses a wide range of antifungal action: it is active concerning Candida spp. (including the strains of C. krusei steady against a flukonazol, and resistant strains of C. glabrata and C. albicans), and also shows fungicidal effect concerning all studied Aspergillus spp strains. and the pathogenic fungi which became urgent recently including Scedosporium spp. or Fusarium spp., which restrictedly are sensitive to the existing antifungal means.

Clinical performance of a vorikonazol was shown at the infections caused by Aspergillus spp., including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis, and also concerning limited number of strains of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

Other fungal infections at which it was applied вориконазол (sometimes with the partial or full answer) included separate cases of the 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.

Activity of a vorikonazol of in vitro concerning clinical strains of Acremonium spp is shown., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. Growth of the majority of strains was suppressed at concentration of a vorikonazol from 0,05 mkg/ml to 2 mkg/ml.

Also activity of a vorikonazol of in vitro concerning Curvularia spp is revealed. and Sporothrix spp., however clinical value of this effect is unknown.

Pharmacokinetics. General characteristic. Pharmacokinetic parameters of a vorikonazol are characterized by considerable interindividual variability.

The pharmacokinetics of a vorikonazol is nonlinear due to saturation of his metabolism. At increase in a dose the disproportionate (more expressed) increase in the area under a curve "concentration time" (AUCt) is observed. Increase in a peroral dose from 200 mg 2 times a day to 300 mg 2 times a day leads to increase in AUCt on average by 2,5 times. At intravenous administration or intake of the sating doses of a vorikonazol its concentration in a blood plasma comes nearer to equilibrium during the first 24 h. If drug is appointed by 2 times a day in averages (but not in sating) doses, then there is cumulation of a vorikonazol, and equilibrium concentration are reached by 6th day at most of patients.

Absorption and distribution

Vorikonazol is quickly and almost completely soaked up after intake: the maximum concentration in a blood plasma (Cmax) is reached in 1-2 h after reception. Bioavailability of a vorikonazol at intake makes 96%. At repeated reception with food with high content of Cmax and AUCt fats decrease by 34% and 24%, respectively. Absorption of a vorikonazol does not depend from рН a gastric juice.

The average volume of distribution of a vorikonazol in an equilibrium state makes about 4,6 l/kg that indicates active distribution of a vorikonazol in fabric. Linkng with proteins of a blood plasma makes 58%.

Vorikonazol gets through a blood-brain barrier (GEB) and is defined in cerebrospinal fluid.

Metabolism

According to data of the researches in vitro вориконазол it is metabolized under the influence of isoenzymes of CYP2C19, CYP2C9, CYP3A4. An important role in metabolism of a vorikonazol is played by CYP2C19 isoenzyme showing the expressed genetic polymorphism in this connection the lowered metabolism of a vorikonazol is possible at 15-20% of representatives of an Asian origin and at 3-5% of representatives of Caucasian and negroid races. It is established that at patients with the lowered metabolism of AUCt of a vorikonazol on average is 4 times higher, than at homozygous patients with high metabolism. At heterozygous patients with high metabolism of AUCt the vorikonazola is on average twice higher, than at homozygous.

The main metabolite of a vorikonazol is N-oxide which share makes about 72% of total quantity of the metabolites circulating in a blood plasma with a radioactive label. This metabolite has the minimum antifungal activity and does not make a contribution to clinical effect of a vorikonazol.

Removal

Vorikonazol is brought in the form of metabolites after biotransformation in a liver; in not changed look kidneys remove less than 2% of the entered drug dose.

After repeated intake or intravenous administration in urine about 83% and 80% of a dose of drug, respectively are found. The most part (> 94%) the general dose is removed during the first 96 h after intake and intravenous administration.

The elimination half-life (T1/2) of a vorikonazol depends on a dose and makes about 6 h at administration of drug inside in a dose of 200 mg. Due to the nonlinearity of pharmacokinetics the size T1/2 does not allow to predict cumulation or removal of a vorikonazol.

Pharmacokinetics in special groups

Floor

At repeated reception of a vorikonazol in Cmax and AUCt at healthy young women were for 83% and 113% respectively above, than at healthy young men (18-45 years). Significant distinctions of Cmax and AUCt at healthy elderly men and healthy elderly women

(≥ 65 years) is not present. In a blood plasma women had an equilibrium concentration of a vorikonazol for 100% and 91% above, than at men after administration of drug in the form of tablets or suspension, respectively. There is no need of dose adjustment of a vorikonazol depending on a floor. Concentration in a blood plasma at men and women are similar.

Age

At repeated reception of a vorikonazol in the form of tablets in Cmax and AUCt at healthy elderly men (≥ 65 years) for 61% and 86% is respectively higher, than at healthy young men (18-45 years). Healthy elderly women (≥ 65 years) and healthy young women (18-45 years) have no significant distinctions of Cmax and AUCt. There is no need of dose adjustment of a vorikonazol depending on age.

The profile of safety of a vorikonazol at young and elderly patients does not differ therefore dose adjustment at use for patients of advanced age is not required.

Children

The recommended dose of a vorikonazol for intake to children is based on data of the pharmacokinetic analysis (47 immunocompromised children aged from 2 up to 12 years of the receiving from 4 to 6 mg/kg of a vorikonazol in the form of suspension 2 times a day). Comparative pharmacokinetic researches showed that for achievement at children of the concentration of drug comparable to that at introduction of a maintenance dose of a vorikonazol for intake of adult 200 mg 2 times a day, for children are required the same dose of a vorikonazol for intake (200 mg 2 times a day, regardless of body weight). It is noted that bioavailability of a vorikonazol directly depends on the body weight of the patient – the body weight of the child is higher, the bioavailability and vice versa is more. The obtained data demonstrate that dose adjustment at reception of a vorikonazol aged from 2 up to 12 years in a dose of 200 mg 2 times a day is not required from children. Nevertheless bioavailability of drug at intake at children can be limited to disturbance of absorption and rather low body weight at this age. According to results of the population pharmacokinetic analysis introduction of the sating dose, and also dose adjustment of a vorikonazol depending on age for children in the age range from 2 to 12 years is not required.



Renal failure

At a single dose of a vorikonazol inside in a dose of 200 mg patients with normal function of kidneys and patients with a renal failure from easy (the clearance of creatinine (CC) <41-60 ml/min.) to heavy (KK <20 ml/min.) of degree drug pharmacokinetics significantly does not depend on degree of a renal failure. Linkng of a vorikonazol with proteins of a blood plasma is approximately identical at patients with various degree of a renal failure (see the sections "Route of Administration and Doses" and "Special Instructions").

Abnormal liver function

After a single dose in drug in a dose of 200 mg of AUCt the vorikonazola at patients with the easy or moderately expressed severity of cirrhosis (classes A and B on classification of Chayld-Pyyu) was 233% higher, than at patients with normal function of a liver. The abnormal liver function does not influence linkng of a vorikonazol with proteins of a blood plasma.

At multiple dose of drug in AUCt the vorikonazola is comparable at the patients with moderately expressed cirrhosis (a class B on classification of Chayld-Pyyu) receiving drug in a maintenance dose of 100 mg of 2 times/days and at the patients with normal function of a liver receiving вориконазол in a dose of 200 mg 2 times a day. Patients with heavy cirrhosis (a class C on classification of Chayld-Pyyu) have no data on pharmacokinetics of a vorikonazol. Recommendations about a drug dosing see in the section "Route of Administration and Doses".

Indications to use:

Invasive aspergillosis.

Kandidemiya at patients without neutropenia.

Severe invasive forms of candidiasis (including C. krusei).

Gullet candidiasis.

The heavy fungal infections caused by Scedosporium spp and Fusarium spp.

Other heavy invasive fungal infections at intolerance or a refrakternost to other medicines.

Prevention of "breakthrough" fungal infections at patients with reduced function of immune system, fever and a neutropenia from groups of high risk (recipients of allogenic marrow, patients with a leukosis recurrence).

Route of administration and doses:

Inside, for 1 h to food or later 1 h after food.

Before therapy it is necessary to modify such electrolytic disturbances as a hypopotassemia, a hypomagnesiemia and a hypocalcemia (cm also the section "Side effect").

Adult patients

Purpose of the drug Vifend® should be begun with the recommended sating dose that in the first day to achieve concentration in the blood plasma close to equilibrium. Considering the high bioavailability of drug at intake reaching 96% (see the section "Pharmacokinetics"), in the presence of clinical indications it is possible to pass from drug, intravenous on oral administration.


Detailed information on a drug dosing is provided in the table:

Intravenously
Inside

Patients with the body weight of 40 kg and more
Patients with body weight less than 40 kg

The sating dose –

all indications (first 24 h)
6 mg/kg each 12 h (in the first 24 h)
400 mg each 12 h (in the first 24 h)
200 mg each 12 h (in the first 24 h)

Maintenance dose (after the first 24 h)


Prevention of "breakthrough" fungal infections
3 mg/kg each 12 h
200 mg each 12 h
100 mg each 12 h

Severe invasive forms of candidiasis / an invasive aspergillosis / infections caused by Scedosporium and Fusarium/other heavy invasive fungal infections
4 mg/kg each 12 h
200 mg each 12 h
100 mg each 12 h

Kandidemiya at patients without manifestations of a neutropenia
3-4 mg/kg each 12 h
200 mg each 12 h
100 mg each 12 h

Gullet candidiasis
There are no recommendations
200 mg each 12 h
100 mg each 12 h


Selection of a dose for intake

At insufficient efficiency of treatment the maintenance dose of the drug Vifend® for intake can be increased to 300 mg each 12 h. At patients with body weight less than 40 kg the dose can be increased to 150 mg each 12 h.

If the patient does not transfer drug in a high dose, then the maintenance dose for intake is gradually reduced to 200 mg on 50 mg by each 12 h (for patients with body weight less than 40 kg - on 100 mg each 12 h).



Phenytoinum can be applied along with the drug Vifend® if the maintenance dose of the last for intake is increased from 200 mg to 400 mg by each 12 h (from 100 mg to 200 mg each 12 h at patients with body weight less than 40 kg); (see the sections "Special Instructions" and "Interaction with Other Medicines").

At simultaneous use of a vorikonazol and efavirenz it is necessary to increase a maintenance dose of a vorikonazol to 400 mg each 12 h.

Duration of treatment depends on clinical effect and results of the laboratory analysis.

Renal failure

The renal failure does not influence pharmacokinetics of a vorikonazol at intake. In this regard dose adjustment of a vorikonazol for intake from patients with a lung or the expressed renal failure is not required.

Abnormal liver function

At the acute injury of a liver which is shown increase in activity of "hepatic" transaminases: alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant), dose adjustment is not required, but it is recommended to continue control of indicators of function of a liver.

Patients with easy or medium-weight abnormal liver functions (classes A and B on classification of Chayld-Pyyu) should appoint the standard sating drug Vifend® dose, and a maintenance dose to reduce twice. Patients with the expressed abnormal liver function (a stage With on classification of Chayld-Pyyu) should appoint the drug Vifend® only when the expected advantage exceeds possible risk, and under constant control for the purpose of identification of signs of toxic effect of drug.

Elderly patients

Dose adjustment is not required from elderly people.

Children

Efficiency and safety of a vorikonazol at children are aged younger than 2 years are not established (see the section "Pharmacodynamics"). In this regard the drug Vifend® is not recommended to children to appoint younger than 2 years.

Drug in the form of tablets is appointed to children if the child can swallow of tablets.

The recommended dose:

Dose for children from 2 to 12 years
Intravenously *
Inside **

7 mg/kg 2 times a day
200 mg 2 times a day


* – on the basis of the population pharmacokinetic analysis of the data obtained at a research with participation of 82 immunocompromised children aged from 2 up to 12 years;

** – on the basis of the population pharmacokinetic analysis of the data obtained at a research with participation of 47 immunocompromised children aged from 2 up to 12 years.

If the child can swallow of tablets, then the dose of drug is rounded to the next dose in mg/kg, by multiple 50 mg, and appoint in the form of the whole tablets.

The pharmacokinetics and portability of higher doses of a vorikonazol for intake at children were not studied.

Recommendations about use of the drug Vifend® for children are made on the basis of researches of its use in the form of powder for preparation of suspension for intake. Bioequivalence of the drug Vifend® in the form of powder for preparation of suspension for intake and tablets at use for children was not studied. Considering that at children passing of food through digestive tract is slowed down, it is quite probable that absorption of a vorikonazol at intake in the form of tablets will be other, than at adults.

Use of a vorikonazol for children aged from 2 up to 12 years with abnormal liver functions or kidneys was not studied.

Teenagers aged from 12 up to 18 years

Drug is dosed the same as for adults.

Features of use:

Sampling for cultural and other laboratory researches (a serology, a histopathology) for the purpose of allocation and identification of activators should be made prior to treatment. Therapy can be begun before obtaining results cultural and other laboratory researches, however at their existence treatment should be corrected as appropriate.

The clinical strains of microorganisms having hyposensitivity to a vorikonazol are allocated. However the increased minimum overwhelming concentration (MOC) not always allow to predict clinical inefficiency: cases when вориконазол it was effective at the patients infected with the microorganisms steady against other azoles are known. It is difficult to estimate correlation between activity of a vorikonazol in the conditions of in vitro and clinical results of treatment, considering complexity of patients who were included in clinical trials. The boundary concentration of a vorikonazol allowing to estimate sensitivity to this drug are not established.

Hypersensitivity

Vorikonazol it is necessary to appoint with care the patient with hypersensitivity to other azoles.

The undesirable phenomena from cardiovascular system

Use of a vorikonazol is connected with lengthening of an interval of QT on the electrocardiogram that is followed by exceptional cases of blinking/trembling of ventricles at seriously ill patients of patients with multiple factors of risk, such as cardiotoxic chemotherapy, cardiomyopathy, hypopotassemia and the accompanying therapy which could promote development of this complication.

Hepatotoxic

At treatment vorikonazoly cases of serious reactions from a liver are observed infrequent (0,1 - 1%), including clinically shown hepatitis, a cholestasia and pechenochnokletochny insufficiency, including with a lethal outcome. The undesirable phenomena from a liver are observed, generally at patients with serious diseases, mainly, of malignant tumors of blood. At patients without any risk factors passing reactions from a liver are observed, including hepatitis and jaundice. Abnormal liver functions are usually reversible and pass after the treatment termination.

Monitoring of function of a liver. During treatment vorikonazoly it is recommended to control constantly function of a liver, in particular, to carry out hepatic tests and definition of bilirubin. At emergence of clinical signs of an abnormal liver function which can be connected with therapy vorikonazoly it is necessary to discuss expediency of the termination of treatment (see the section "Route of Administration and Doses"). Control of function of a liver needs to be carried out both at children, and at adults.

Visual disturbances

According to post-market researches it is reported about development of cases of the visual disturbances remaining long time, in particular, emergence of "veil" before eyes, an optic neuritis and a papilledema. It should be noted that these disturbances develop most often at seriously ill patients of patients and/or receiving the accompanying therapy which can cause the similar undesirable phenomena.

The undesirable phenomena from kidneys

At seriously ill patients of the patients receiving вориконазол cases of development of an acute renal failure were noted that it was probably connected with therapy of the basic or associated diseases, nefrotoksichny medicines.

Monitoring of function of kidneys. Patients should be observed for the purpose of identification of signs of a renal failure. For this purpose it is necessary to conduct laboratory researches, in particular, to define concentration of creatinine in blood serum (see the section "Route of Administration and Doses").

Monitoring of function of a pancreas

The adults and children having risk factors of development of acute pancreatitis (recent chemotherapy, transplantation of haematopoietic stem cells) have to undergo inspection for the solution of a question of therapy vorikonazoly.

The undesirable phenomena from skin

Not often at treatment vorikonazoly at patients exfoliative skin reactions, such as Stephens-Johnson's syndrome develop. If at the patient exfoliative skin reactions develop, then вориконазол it is necessary to cancel.

Besides, prolonged use of a vorikonazol is followed by skin reactions of photosensitivity. During treatment by the patient it is recommended to avoid intensive or long influence of direct sunshine. At patients with skin reactions of photosensitivity and accessory factors of risk it is reported about development of a planocellular carcinoma cutaneum and a melanoma against the background of long therapy. If at the patient the damages of skin connected with a planocellular carcinoma cutaneum or a melanoma develop, then it is necessary to consider a question of the therapy termination vorikonazoly.

Use for children

Efficiency and safety of use of a vorikonazol for children under 2 years were not studied. Vorikonazol is shown for use for children aged from 2 years and is more senior at constant control of function of a liver. Bioavailability of a vorikonazol at intake at children aged from 2 up to 12 years can be reduced due to disturbance of absorption or at the expense of a body underweight. In such cases intravenous administration of a vorikonazol is shown.

Methadone (CYP3A4 isoenzyme substrate)

Increase in concentration of methadone in a blood plasma leads to manifestation of toxic effects, including lengthening of an interval of QT. At simultaneous use of a vorikonazol and methadone it is necessary to watch closely manifestation of undesirable and toxic effects. If necessary the dose of methadone can be lowered (see the section "Interaction with Other Medicines").

Narcotic analgetics of short action (CYP3A4 isoenzyme substrates)

At simultaneous use of a vorikonazol and alfentanil or its structural analogs (sufentanil), it is necessary to provide a dose decline of the last. As an alfentanil elimination half-life at its simultaneous introduction with vorikonazoly

increases by 4 times, careful monitoring of the undesirable phenomena connected using narcotic analgetics including more long monitoring of function of breath is necessary.

Oxycodone (CYP3A4 isoenzyme substrate)

It is necessary to provide a possibility of a dose decline of oxycodone and other narcotic analgetics of long action which are metabolized by an isoenzyme of CYP3A4 (hydrocodon) at simultaneous use with vorikonazoly. It is necessary to carry out careful monitoring of the undesirable phenomena connected using narcotic analgetics (see the section "Interaction with Other Medicines").
Phenytoinum (powerful inductor of P450 cytochrome and substrate of an isoenzyme CYP2C9)

At simultaneous use of Phenytoinum and vorikonazol it is recommended to exercise constant control of concentration of Phenytoinum. Whenever possible it is necessary to avoid simultaneous use of a vorikonazol and Phenytoinum unless the expected advantage exceeds possible risk (see the section "Interaction with Other Medicines").

Ritonavir (powerful inductor of P450 cytochrome, inhibitor and substrate of an isoenzyme CYP3A4)

It is necessary to apply at the same time вориконазол and ритонавир in low doses (100 mg 2 times a day) only if the expected advantage of reception of a vorikonazol considerably exceeds risk from their combined use (see sections of "Contraindication" and "Interaction with Other Medicines").

Efavirenz (nenukleozidny inhibitor of the return transcriptase, P450 cytochrome inductor, inhibitor and substrate of an isoenzyme CYP3A4)

In case of simultaneous use of a vorikonazol and an efavirenz it is necessary to increase a dose of a vorikonazol to 400 mg 2 times a day, and the dose of an efavirenz has to be lowered to 300 mg each 24 h (see the sections "Route of Administration and Doses" and "Interaction with Other Medicines").


Influence on ability to drive the car and to use a difficult technique

Vorikonazol can cause passing and reversible vision disorders, including emergence of "veil" before eyes, disturbance/strengthening of visual perception and/or photophobia. In the presence of such symptoms patients have to avoid performance of potentially dangerous actions, in particular, of driving or use of a difficult technique. At reception of a vorikonazol patients should not drive the car at night.

Side effects:

Data on safety of a vorikonazol are based on results of a research of more than 2000 people presented by heterogeneous population (patients with zlokachastvenny new growths of blood, HIV-positive patients with candidiasis of a gullet and refractory fungal infections, patients without neutropenia with a kandidemiya or an aspergillosis, and also healthy volunteers). 561 patients have a therapy vorikonazoly lasted more than 12 weeks, 136 patients received вориконазол more than 6 months.

The undesirable phenomena which were observed at use of drug and, perhaps are listed below, connected with treatment. The most widespread undesirable reactions are visual disturbances, fever, rash, vomiting, nausea, diarrhea, a headache, peripheral hypostases and an abdominal pain. Undesirable reactions usually were easily or are moderately expressed. Clinically significant dependence of safety of drug on age, race or a floor is not revealed.

* Criteria for evaluation of frequency: very frequent ³ 10%; frequent - ³1% and <10%;

not frequent - ³ 0.1% and <1%; rare-> 0,01% and <0,1%, very rare <0,01%.

System of bodies
Undesirable reaction

Laboratory indicators

Frequent
abnormal liver function (including increase in activity of nuclear heating plant, ALT, alkaline phosphatase, gamma глутамилтрансферазы, lactate dehydrogenases, concentration of bilirubin), increase in concentration of creatinine in a blood plasma

Not frequent
lengthening of an interval of QT, increase in residual nitrogen of urea, hypercholesterolemia

From cardiovascular system

Very frequent
peripheral hypostases

Frequent
lowering of arterial pressure, thrombophlebitis, phlebitis

Not frequent
fibrillation of ventricles, ventricular arrhythmia, syncope, atrial arrhythmia, supraventricular arrhythmia, supraventricular tachycardia, bradycardia, tachycardia

Rare
ventricular tachycardia (including trembling of ventricles), a total atrioventricular block, blockade of a leg of a ventriculonector, nodal arrhythmias, a lymphangitis

From system of a hemopoiesis and lymphatic system

Frequent
pancytopenia, oppression of a marrowy hemopoiesis, thrombocytopenia, leukopenia, purpura, anemia (including, macrocytic, microcytic, normotsitarny, megaloblastny, aplastic)

Not frequent
syndrome of the disseminated intravascular coagulation, lymphadenopathy, agranulocytosis, eosinophilia

From a nervous system

Very frequent
headache

Frequent
dizziness, confusion of consciousness, agitation, tremor, paresthesias

Not frequent
brain hypostasis, ataxy, diplopia, вертиго, hypesthesia

Rare
spasms, encephalopathy, syndrome to Giyenna-Barra, extrapyramidal frustration, drowsiness during infusion

From an organ of sight

Very frequent
visual disturbances (including disturbance/strengthening of visual perception, emergence of "veil" before eyes, change of color perception, photophobia)

Not frequent
papilledema, sclerite, blepharitis, optic neuritis, nystagmus

Rare
hemorrhage in a mesh cover of an eye, an atrophy of an optic nerve, opacification of a cornea, okulogirny crisis

From an acoustic organ and vestibular mechanism

Not frequent
gipoakuziya, sonitus

From respiratory system, a thorax and a mediastinum:

Frequent
respiratory distress syndrome, fluid lungs, breath disturbance, stethalgia

From digestive tract

Very frequent
nausea, vomiting, diarrhea, abdominal pain

Not frequent
lock, duodenitis, dyspepsia, ulitis, glossitis, pancreatitis, paraglossa, peritonitis

Rare
disturbance of flavoring perception

From urinogenital system

Frequent
acute renal failure, hamaturia

Not frequent
albuminuria, nephrite

Rare
necrosis of renal tubules

From skin and hypodermic fabrics

Very frequent
rash

Frequent
face edema, itch, makulopapulezny rash, photosensitization, alopecia, exfoliative dermatitis, cheilitis, erythema

Not frequent
Stephens-Johnson's syndrome, Quincke's disease, the fixed medicinal rash, eczema, psoriasis, small tortoiseshell

Rare
diskoidny lupus erythematosus, multiformny erythema, toxic epidermal necrolysis, pseudo-porphyria

From a musculoskeletal system and connecting fabric

Frequent
dorsodynia

Not frequent
arthritis

Rare
hypertension

From endocrine system

Not frequent
insufficiency of bark of adrenal glands

Rare
hyperthyroidism, hypothyroidism

Disturbances of metabolism and food

Frequent
hypopotassemia, hypoglycemia

Infections and invasions

Frequent
gastroenteritis, grippopodobny syndrome

Rare
pseudomembranous colitis

General and local reactions

Very frequent
fever

Frequent
fever, adynamy, reaction/inflammation in an injection site

From immune system

Frequent
sinusitis

Not frequent
allergic reactions, anaphylactoid reactions

From gepatobiliarny system

Frequent
jaundice, cholestatic jaundice

Not frequent
cholecystitis, cholelithiasis, increase in a liver, hepatitis, liver failure

Rare
hepatic coma

Mental disorders

Frequent
hallucinations, depression, alarm

Rare
sleeplessness

Visual disturbances

At treatment vorikonazoly approximately at 21% of patients disturbance of visual perception is observed: sight misting, change of color sight or photophobia. Vision disorders are passing and completely reversible; in most cases they spontaneously disappear within 60 min. At repeated use of a vorikonazol easing of their expressiveness is noted. Visual disturbances are usually easily expressed, seldom demand the termination of treatment and do not lead to any remote effects.

The mechanism of action of a vorikonazol is unknown though a target organ, most often, is the mesh cover of an eye. It is established what вориконазол reduces amplitude of waves on the electroretinogram (ERG) at healthy volunteers. These changes of the ERG did not accrue at continuation of treatment within 29 days and completely disappeared after cancellation of a vorikonazol.

Long therapy vorikonazoly (on average within 169 days) patients with a paracoccidioidosis did not render clinically significant effect on visual function that was confirmed by results of tests for visual acuity, visual fields, color perception and contrast sensitivity.

Skin reactions
At therapy vorikonazoly skin reactions, generally at the patients with serious basic diseases who are at the same time accepting other medicines often develop. It was in most cases noted easily or moderately expressed skin rash.

Not often at treatment vorikonazoly heavy skin reactions, including Stephens-Johnson's syndrome, a toxic epidermal necrolysis and a multiformny erythema developed. At emergence of rash it is necessary to watch the patient constantly, and when progressing skin rashes it is reasonable to cancel вориконазол. At patients, it is long receiving вориконазол, skin reactions of photosensitivity can develop (see the section "Special Instructions").

Indicators of function of a liver

Frequency of clinically significant increase in activity of "hepatic" transaminases at the patients receiving вориконазол makes 13,4%. In most cases indicators of function of a liver are normalized as at continuation of treatment without change of a dose or after its correction, and after the therapy termination. At use of a vorikonazol cases of a heavy hepatotoxic (jaundice, hepatitis and the pechenochnokletochny insufficiency leading to death) at patients with serious basic diseases were not often observed.

Use for children

In clinical trials of safety of use of a vorikonazol with participation of 245 children aged from 2 up to 12 years it is established that undesirable effects of drug at children are similar to that at adults. During the post-market researches development of pancreatitis in children against the background of therapy vorikonazoly, and also more frequent emergence of skin reactions is revealed.

Interaction with other medicines:

Influence of other medicines on pharmacokinetics of a vorikonazol

Vorikonazol is metabolized under the influence of P450 cytochrome isoenzymes - CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inductors of these isoenzymes can cause, respectively, increase or decrease in concentration of a vorikonazol in a blood plasma.

Simultaneous use of a vorikonazol is contraindicated with the following medicinal drugs:

The St. John's Wort which is made a hole (the inductor of P450 cytochrome and P-glycoprotein)
In independent researches on healthy volunteers it is shown that the St. John's Wort which is made a hole renders the short initial inhibiting effect on metabolism of a vorikonazol which its activation follows. Simultaneous use of the vorikonazol and St. John's Wort which is made a hole contraindicated (see the section "Contraindications").

Concentration of a vorikonazol in a blood plasma considerably decreases at simultaneous use with the following medicines:
Rifampicin (powerful inductor of P450 cytochrome)

Rifampicin (600 mg of 1 times a day) lowers Cmax and AUCt of a vorikonazol by 93% and 96%, respectively. Simultaneous use of a vorikonazol and rifampicin contraindicated (see the section "Contraindications").

Ritonavir (powerful inductor of P450 cytochrome, inhibitor and substrate of an isoenzyme CYP3A4)

The effect of the combined use of a peroral form of a vorikonazol (200 mg 2 times a day), and also high (400 mg) and a low dose (100 mg) of a peroral form of a ritonavir was studied in two researches on healthy volunteers. Reception of a ritonavir in a dose of 400 mg each 12 h lowered Cmax and AUCt of a vorikonazol at intake on average by 66% and 82%, respectively. Reception of a ritonavir in a dose of 100 mg each 12 h lowered Cmax and AUCt of a vorikonazol at intake on average by 24% and 39%, respectively. It is established that repeated reception of a vorikonazol inside does not render the expressed effect on Cmax in an equilibrium condition and AUCt of the ritonavir accepted in a dose of 400 mg each 12 h.

At the same time, steady decrease in Cmax and AUCt by 25% and 13% was respectively observed at reception of a ritonavir in a dose of 100 mg each 12 h. Simultaneous use of a vorikonazol and ritonavir (400 mg each 12 h) is contraindicated (see the section "Contraindications"). Simultaneous use of a vorikonazol and a ritonavir in a dose of 100 mg each 12 h should be avoided.

Carbamazepine it is also long the operating barbiturates (including phenobarbital)
(powerful inductors of P450 cytochrome)

Interaction of a vorikonazol with carbamazepine is also long the operating barbiturates (phenobarbital) was not studied, however is high-probability that these drugs considerably reduce concentration of a vorikonazol in a blood plasma. Simultaneous use of a vorikonazol with carbamazepine is also long the operating barbiturates contraindicated (see the section "Contraindications").

Considering insignificant pharmacokinetic interaction or lack of significant interaction, correction of doses of the following medicines is not required:

Cimetidinum (nonspecific inhibitor of P450 cytochrome, and also raises рН a gastric juice)

Cimetidinum (400 mg 2 times a day) causes increase in Cmax and AUCt of a vorikonazol for 18% and 23%, respectively. Dose adjustment of a vorikonazol is not required.

Ranitidine (raises рН a gastric juice)

Ranitidine (150 mg 2 times a day) does not exert significant impact on Cmax and AUCt of a vorikonazol.

Antibiotics of group of macroleads

Erythromycin (CYP3A4 isoenzyme inhibitor; 1 g 2 times a day) and azithromycin (500 mg of 1 times a day) have no significant effect on Cmax and AUCt of a vorikonazol.

Action of a vorikonazol on pharmacokinetics of other medicines

Vorikonazol inhibits activity of isoenzymes of P450 cytochrome – CYP2C19, CYP2C9 and CYP3A4, – and can increase plasma concentration of substances which are metabolized with participation of isoenzymes of P450 cytochrome.

Contraindicated simultaneous use of a vorikonazol with the following medicines:

Terfenadin, астемизол, цизаприд, Pimozidum and quinidine
(CYP3A4 isoenzyme substrates)

Interaction of a vorikonazol with terfenadiny, astemizoly, tsizapridy, Pimozidum and quinidine was not studied. However it is high-probability that simultaneous use of a vorikonazol with these drugs can lead to increase in their concentration in a blood plasma. It, in turn, can cause lengthening of an interval of QT and, in rare instances, lead to development of blinking/trembling of ventricles. Simultaneous use of a vorikonazol with terfenadiny, astemizoly, tsizapridy, Pimozidum and quinidine contraindicated (see the section "Contraindications").

Sirolimus (CYP3A4 isoenzyme substrate)

Vorikonazol raises Cmax and AUCt of a sirolimus (2 mg once) for 556% and 1014%, respectively. Simultaneous use of a vorikonazol and sirolimus is contraindicated (see the section "Contraindications").

Ergot alkaloids (CYP3A4 isoenzyme substrates)

Interaction of a vorikonazol with ergot alkaloids (ergotamine and dihydroergotamine) was not studied, however is high-probability that вориконазол can cause increase in concentration of these drugs in a blood plasma and development of an ergotism. Simultaneous use of alkaloids of an ergot with vorikonazoly is contraindicated (see the section "Contraindications").

Interaction with vorikonazoly can lead to increase in concentration in a blood plasma of the following medicines which are listed below. In this regard at their simultaneous use constant observation and/or correction of doses are necessary:

Cyclosporine (CYP3A4 isoenzyme substrate)

At the patients who transferred transplantation of a kidney and being in a stable state вориконазол raises Cmax and AUCt of cyclosporine at least for 13% and 70% respectively. At purpose of a vorikonazol the patients receiving cyclosporine are recommended to reduce a cyclosporine dose twice and to control its concentration in

to blood plasma. Increase in concentration of cyclosporine is followed by nephrotoxicity. After cancellation of a vorikonazol it is necessary to control concentration of cyclosporine and if necessary to increase its dose.

Takrolimus (CYP3A4 isoenzyme substrate)

Vorikonazol raises Cmax and AUCt (the area under a curve "concentration time" to the last quantitative measurement) a takrolimusa (0,1 mg/kg once) for 117% and 221%, respectively. At purpose of a vorikonazol the patients receiving такролимус are recommended to reduce a dose of the last to one third and to control its concentration in a blood plasma. Increase in concentration of a takrolimus is followed by nephrotoxicity. After cancellation of a vorikonazol it is necessary to control concentration of a takrolimus and if necessary to increase its dose.

Methadone (CYP3A4 isoenzyme substrate)

Repeated introduction of a vorikonazol in (400 mg each 12 h in the first days and on 200 mg each 12 h in the next 4 days) raises Cmax and AUCt pharmacological of active R-methadone for 31% and 47%, respectively, at the patients receiving a maintenance dose of methadone of 30-100 mg a day (see the section "Special Instructions").

Narcotic analgetics of short action (CYP3A4 isoenzyme substrates)

Constant use of a vorikonazol inside by 6 times increases AUC alfentanil in a single dose. At simultaneous use of a vorikonazol and alfentanil or other narcotic analgetics of short action, – its structural analogs (for example, sufentanil), – it is necessary to provide a dose decline of the last.

Fentanyl (CYP3A4 isoenzyme substrate)

Simultaneous use of a vorikonazol (400 mg each 12 h in the first days and on 200 mg each 12 h in the next days) and fentanyl in a single dose of 5 mkg/kg intravenously raises AUC fentanyl on average by 1,4 times (from 1,12 to 1,60 times). At combined use of a vorikonazol and fentanyl patients have to be under constant observation for the prevention of oppression of function of breath or other side effects connected with fentanyl reception, and if necessary the dose of fentanyl has to be lowered.

Oxycodone (CYP3A4 isoenzyme substrate)

Simultaneous use of a vorikonazol in (400 mg each 12 h in the first days and on 200 mg each 12 h in the next 2-4 days) and oxycodone orally in a single dose of 10 mg for the 3rd days raises Cmax of oxycodone by 1,7 times (from 1,4 to 2,2 times) and AUC oxycodone by 3,6 times (from 2,7 to 5,6 times). The oxycodone elimination half-life also increases twice (from 1,4 to 2,5 times). To avoid the undesirable effects caused by narcotic analgetics the oxycodone dose decline at joint therapy with vorikonazoly can be required. It is recommended to carry out expanded repeated monitoring of the undesirable effects connected with administration of oxycodone and other narcotic analgetics of short action which are metabolized under the influence of CYP3A4 isoenzyme.

Warfarin (CYP2C9 isoenzyme substrate)

Simultaneous use of a vorikonazol (300 mg 2 times a day) with warfarin (30 mg once) was followed by increase in the maximum prothrombin time by 93%. At simultaneous use of warfarin and a vorikonazol it is recommended to control a prothrombin time.

Other peroral anticoagulants, for example, фенпрокумон, аценокумарол (substrates of isoenzymes CYP2C9, CYP3A4)

Vorikonazol can cause increase in concentration of derivatives of coumarin in a blood plasma and a prothrombin time. If the patient receiving coumarin drugs appoint вориконазол, it is necessary to control a prothrombin time with short intervals and as appropriate to select doses of anticoagulants.

Sulphonylurea derivatives (CYP2C9 isoenzyme substrates)

Vorikonazol can increase concentration of derivatives of sulphonylurea (Tolbutamidum, a glipizid and Glyburidum) in a blood plasma and to cause a hypoglycemia. At simultaneous use of a vorikonazol with the specified drugs it is necessary to control carefully concentration of glucose in blood.

Statines (CYP3A4 isoenzyme substrates)

In vitro вориконазол inhibits metabolism of a lovastatin in microsomes of a liver of the person and can cause increase in plasma concentration of statines which are metabolized under the influence of CYP3A4 isoenzyme. At simultaneous use of a vorikonazol and statines it is recommended to estimate expediency of dose adjustment of statines. Increase in concentration of statines sometimes is followed by development of a rabdomioliz.

Benzodiazepines (CYP3A4 isoenzyme substrates)

In vitro вориконазол inhibits metabolism of midazolam in microsomes of a liver of the person and can cause increase in plasma concentration of benzodiazepines (midazolam, a triazolam, an alprazolam) which are metabolized under the influence of CYP3A4 isoenzyme, and development of the prolonged sedation. At simultaneous use of a vorikonazol and benzodiazepines it is recommended to estimate expediency of dose adjustment of benzodiazepines.

Periwinkle alkaloids (CYP3A4 isoenzyme substrates)

Vorikonazol can increase the content of alkaloids of a periwinkle (Vincristinum and vinblastine) in a blood plasma and to cause a neurotoxicity. At simultaneous use of a vorikonazol and alkaloids of a periwinkle it is recommended to estimate expediency of dose adjustment of alkaloids of a periwinkle.

Non-steroidal anti-inflammatory drugs (NPVP)

Vorikonazol raises Cmax and AUCt of an ibuprofen (400 mg once) for 20% and 100%, respectively, and Cmax and AUCt of diclofenac (50 mg once) – for 114% and 78%, respectively. In case of simultaneous use of a vorikonazol and NPVP of patients it is necessary to observe for the purpose of identification of possible toxic effects and if necessary to adjust NPVP dose.

At simultaneous use of a vorikonazol with the following medicines of significant pharmacokinetic interaction it is not revealed,

therefore correction of their dose is not required:

Prednisolonum (CYP3A4 isoenzyme substrate)

Vorikonazol raises Cmax and AUCt of Prednisolonum (60 mg once) for 11% and 34% respectively. Dose adjustment is not required.

Digoxin (the transport mediated by the R-glycoprotein)

Vorikonazol has no significant effect on Cmax and AUCt of digoxin (0,25 mg of 1 times a day).

Mikofenolovy acid (substrate-diphosphate-glyukuroniltransferazy uridine-5)

Vorikonazol does not exert impact on Cmax and AUCt of mikofenolovy acid (1 g once).

Bilateral interaction

Phenytoinum (powerful inductor of P450 cytochrome and substrate of an isoenzyme CYP2C9)

Simultaneous use of a vorikonazol and Phenytoinum should be avoided unless the expected advantage exceeds possible risk.

Phenytoinum (300 mg of 1 times a day) lowers Cmax and AUCt of a vorikonazol by 49% and 69% respectively. Vorikonazol (400 mg of 1 time a day) raises Cmax and AUCt of Phenytoinum (300 mg of 1 times a day) for 67% and 81%, respectively. At simultaneous use of Phenytoinum with vorikonazoly it is recommended to control concentration of Phenytoinum in a blood plasma. Phenytoinum can be applied together with vorikonazoly if the maintenance dose of the last is increased to 5 mg/kg each 12 h intravenously or from 200 to 400 mg each 12 h inside (from 100 to 200 mg each 12 h inside at patients with body weight less than 40 kg; see the section "Route of Administration and Doses").



Omeprazol (inhibitor of an isoenzyme CYP2C19 and substrate of isoenzymes of CYP2C19 and CYP3A4)

Omeprazol (40 mg of 1 times a day) raises Cmax and AUCt of a vorikonazol for 15% and 41%, respectively. Dose adjustment of a vorikonazol is not recommended. Vorikonazol raises Cmax and AUCt of an omeprazol for 116% and 280%, respectively. At purpose of a vorikonazol the patients receiving омепразол are recommended to reduce a dose of the last twice. Vorikonazol can also inhibit metabolism of other inhibitors of a proton pomp which are CYP2C19 isoenzyme substrates.

Oral contraceptives (CYP3A4 isoenzyme substrates)

Simultaneous use of a vorikonazol and oral contraceptives (1 mg of Norethisteronum and 0,035 mg of ethinylestradiol of 1 races a day) at healthy women led to increase in Cmax and AUCt of Norethisteronum by 15% and 53%, respectively, and ethinylestradiol – for 36% and 61%, respectively. At this Cmax and AUCt of a vorikonazol increased by 14% and 46%, respectively. The low-dosed oral contraceptives were not investigated. As the ratio between Norethisteronum and ethinylestradiol remains approximately identical at interaction with vorikonazoly, it is possible to assume that their contraceptive activity does not change. In case of simultaneous use of a vorikonazol and oral contraceptives it is necessary to carry out monitoring for the purpose of identification of possible undesirable effects.

Indinavir (inhibitor and substrate of an isoenzyme CYP3A4)

Indinavir (800 mg 3 times a day) has no significant effect on Cmax and AUCt of a vorikonazol. Vorikonazol significantly does not influence Cmax, Cmin and AUCt of an indinavir (800 mg 3 times a day).

Other inhibitors of HIV protease
(substrates and inhibitors of an isoenzyme CYP3A4)

The researches in vitro demonstrate to what вориконазол can inhibit metabolism of inhibitors of HIV protease: sakvinavira, amprenavira and nelfinavira. In turn, inhibitors of HIV protease can suppress metabolism of a vorikonazol. In case of simultaneous use of a vorikonazol with inhibitors of HIV protease of patients it is necessary to observe for the purpose of identification of possible toxic effects.

Efavirenz (nenukleozidny inhibitor of the return transcriptase, P450 cytochrome inductor, inhibitor and substrate of an isoenzyme CYP3A4)

In an equilibrium state эфавиренз (400 mg of 1 times a day inside) lowers equilibrium Cmax and AUCt of a vorikonazol on average by 61% and 77%, respectively. Vorikonazol in an equilibrium state (400 mg inside each 12 h in the first day, then 200 mg inside each 12 h within 8 days) raises equilibrium Cmax and AUCt of an efavirenz on average for 38% and 44%, respectively.

Other nenukleozidny inhibitors of the return transcriptase

(inhibitors or inductors of P450 cytochrome and substrates of an isoenzyme CYP3A4)

Delavirdin in the conditions of in vitro can inhibit metabolism of a vorikonazol. Not Virapinum can induce metabolism of a vorikonazol though the similar effect was not studied. Vorikonazol can suppress metabolism of nenukleozidny inhibitors of the return transcriptase. At simultaneous use of a vorikonazol with nenukleozidny inhibitors of the return transcriptase of patients it is necessary to observe for the purpose of identification of possible toxic effects.



Simultaneous use of a vorikonazol is contraindicated with the following medicinal drugs:

Rifabutin (P450 cytochrome inductor)

Rifabutin (300 mg of 1 times a day) lowers Cmax and AUCt of a vorikonazol (200 mg 2 times a day) by 69% and 78%, respectively. At simultaneous use of a rifabutin of Cmax and AUCt of a vorikonazol in a dose of 350 mg 2 times a day made 96% and 68% of indicators at use only of a vorikonazol in a dose of 200 mg 2 times a day. At use of a vorikonazol in a dose of 400 mg 2 times in days of Cmax and AUCt, respectively, for 104% and 87% are higher, than at monotherapy vorikonazoly in a dose of 200 mg 2 times a day. Vorikonazol in a dose of 400 mg 2 times a day raises Cmax and AUCt of a rifabutin for 195% and 331%, respectively. Simultaneous use of a vorikonazol and rifabutin is contraindicated.

Contraindications:

The drug Vifend® is contraindicated to patients with hypersensitivity to a vorikonazol or any other component of drug.

Simultaneous use of the drug Vifend® and substrates of an isoenzyme CYP3A4 – a terfenadin, an astemizol, a tsizaprid, Pimozidum or quinidine contraindicated as increase in concentration of the last in a blood plasma can lead to lengthening of an interval of QT and, in rare instances, to development of trembling/ventricular fibrillation (see the section "Interaction with Other Medicines").

Simultaneous use of the drug Vifend® and sirolimus contraindicated as вориконазол considerably increases concentration of a sirolimus in a blood plasma of healthy people (see the section "Interaction with Other Medicines").

Simultaneous use of the drug Vifend® with rifampicin, carbamazepine is also long the operating barbiturates (phenobarbital) contraindicated as these medicines considerably reduce concentration of a vorikonazol in a blood plasma (see the section "Interaction with Other Medicines").

Simultaneous use of the drug Vifend® with ritonaviry (400 mg each 12 h) is contraindicated as the last considerably reduces concentration of a vorikonazol in a blood plasma of healthy volunteers (see the section "Interaction with Other Medicines").

Simultaneous use of the drug Vifend® and rifabutin (the P450 cytochrome inductor) is contraindicated as рифабутин considerably reduces concentration of a vorikonazol in a blood plasma, and вориконазол increases concentration of a rifabutin.

Simultaneous use of the drug Vifend® and alkaloids of an ergot (ergotamine, dihydroergotamine) which are CYP3A4 isoenzyme substrates is contraindicated as increase in concentration of these substances in a blood plasma can lead to an ergotism (see the section "Interaction with Other Medicines").

Simultaneous use of the vorikonazol and St. John's Wort which is made a hole (the inductor of P450 cytochrome and P-glycoprotein) is contraindicated (see the section "Interaction with Other Medicines").

The drug Vifend® is contraindicated to children aged 2 years are younger.

With care

Hypersensitivity to other drugs - derivatives of azoles.

Heavy degree of insufficiency of function of a liver, heavy degree of insufficiency of function of kidneys.

Vorikonazol it is necessary to apply with care at patients with pro-arhythmic states:

- the inborn or acquired increase in an interval of QT

- a cardiomyopathy, in particular with heart failure

- sinus bradycardia

- existence of symptomatic arrhythmia

- a concomitant use of the drugs causing lengthening of an interval of QT

Electrolytic disturbances, such, as: a hypopotassemia, a hypomagnesiemia and a hypocalcemia it is necessary to control and, if necessary, to adjust prior to therapy vorikonazoly or during therapy.

Pregnancy and period of a lactation

There is no sufficient information about use of a vorikonazol for pregnant women.

In researches on animals it is established that drug has toxic effect on reproductive function. The possible risk for the person is unknown. Vorikonazol it is not necessary to apply at pregnant women unless the expected advantage for mother obviously exceeds possible risk for a fruit. Removal of a vorikonazol with breast milk was not studied. Vorikonazol it is not necessary to apply at the women nursing unless the expected advantage obviously exceeds risk.

Women of reproductive age at use of the drug Vifend® have to use reliable methods of contraception.

Overdose:

It is known of three cases of accidental overdose. All mentioned cases occurred at children to whom the dose of a vorikonazol five times exceeding recommended was intravenously entered.

There is a message on an isolated case of photophobia, lasting 10 minutes.

The antidote of a vorikonazol is unknown. In case of overdose the symptomatic and maintenance therapy is shown.

Vorikonazol is brought during a hemodialysis with clearance of 121 ml/min. In case of overdose the hemodialysis can promote removal of a vorikonazol from an organism.

Storage conditions:

To store at a temperature not above 30 °C. To store in the places unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 50 mg and 200 mg; 2, 7 or 10 tablets in the blister from polyvinylchloride and aluminum foil 1 blister on 2, 7 or 10 tablets; 2, 4 or 8 blisters on 7 tablets; 3, 5 or 10 blisters on 10 tablets in a cardboard pack together with the application instruction