Vikand

General characteristics. Structure:

Active ingredient: 50 mg or 200 mg of a vorikonazol in 1 tablet.

Excipients: lactoses monohydrate, silicon dioxide colloid (aerosil), cellulose microcrystallic, starch corn, povidone, macrogoal 6000 (polyethyleneglycol 6000), кросповидон, talc, magnesium stearate.

Excipients for a cover: hypro rod (hydroxypropyl cellulose), macrogoal 6000 (polyethyleneglycol 6000), titanium dioxide.

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 inhibition of demethylation of the 14a-sterol mediated through fungal P450 cytochrome which is a key stage of biosynthesis of ergosterol. Accumulation of a 14a-metilsterol correlates with the subsequent loss of ergosterol in fungal cellular membranes that causes antifungal activity of a vorikonazol. It was established that вориконазол more селективен concerning isoenzymes of R45o cytochrome of fungi, than concerning various fermental systems of R45o cytochrome of mammals.

In vitro вориконазол possesses a wide range of antifungal action: it is active concerning Candida spp. (including S.'s strains of krusei steady against a flukonazol, and resistant strains of S. of glabrata and S. of 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 (with the partial or full answer) a vorikonazola was shown at the infections caused by Aspergillus spp., including A. flavus, And. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including S. of albicans, S. of glabrata, S. of krusei, S. parapsilosis and S. tropicalis, and also concerning limited number of strains of S. of dubliniensis, S. of inconspicua, and S. of 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. mameffei, 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 capsulation. 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. Influence of a vorikonazol at intake of a maintenance dose of 200 mg (or 100 mg for patients with body weight less than 40 kg) corresponds to influence of a vorikonazol at use intravenously in a dose of 3 mg/kg. At intake of a maintenance dose of 300 mg (or 150 mg for patients with body weight less than 40 kg) influence corresponds to influence of a vorikonazol at intravenous use in a dose of 4 mg/kg.

At reception of the sating doses of a vorikonazol equilibrium concentration is reached 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 sixth 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 (Stakh) is reached in 1-2 h after reception. Bioavailability of a vorikonazol at intake makes 96%. At multiple dose of a vorikonazol with food with high content of fats Stakh and AUCT decrease by 34% and 24%, respectively. Absorption of a vorikonazol does not depend on pH of 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. 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 multiple dose of a vorikonazol inside 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 (TV) a vorikonazola 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 TV, does not allow to predict cumulation or removal of a vorikonazol.

Pharmacokinetics in special groups. Floor. At multiple dose of a vorikonazol inside healthy young women had Stakh and AUCT for 83% and 113% respectively above, than at healthy young men (18-45 years). Stakh and AUCT at healthy elderly men and healthy elderly women (> 65 years) is not present significant distinctions. Equilibrium concentration of a vorikonazol in a blood plasma at women was 100% higher, than at men. 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 multiple dose of a vorikonazol in the form of tablets inside Stakh and AUCT at healthy elderly men (> 65 years) for 61% and 86% is respectively higher, than at healthy young men (18-45 years). Stakh and AUCT healthy elderly women (> 65 years) and have significant distinctions of no healthy young women (18-45 years).

The profile of safety of a vorikonazol at young and elderly patients does not differ. There is no need of dose adjustment of a vorikonazol depending on age.

Children. Estimated general concentration of a vorikonazol at children at intake of a maintenance dose of 9 mg/kg (at most 350 mg) two times a day is comparable to that at adults at reception of a vorikonazol inside in a dose of 200 mg two times a day. Concentration of a vorikonazol at intravenous administration in a dose of 8 mg/kg is twice higher, than at intake in a dose of 9 mg/kg. Bioavailability of a vorikonazol at intake at children can be limited to disturbance of absorption and rather low body weight at this age and in this case intravenous administration can be shown.

At most of teenagers concentration of a vorikonazol in a blood plasma corresponds to this indicator at adult patients. Nevertheless, smaller values of concentration of a vorikonazol in a blood plasma at some teenagers with low body weight in comparison with adults were noted and were closer to values of the same indicator at children. Based on the population pharmacokinetic analysis, teenagers aged from 12 up to 14 years with body weight less than 50 kg have to receive the dose of a vorikonazol recommended for reception at children.

Renal failure. At a single dose of a vorikonazol inside in a dose of 200 mg patients with normal function of kidneys and to patients with a renal failure from easy (the clearance of creatinine (CC) - 41-60 ml/min.) to heavy degree (KK <20 ml/min.) pharmacokinetics of a vorikonazol 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 of a vorikonazol at patients with easy or moderate severity of an abnormal liver function (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 2 times a day 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 severity of a liver failure (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.
• Heavy invasive candidosis infections (including S. 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 group of high risk (recipients of transplantation of haematopoietic stem cells, patients with a leukosis recurrence).
• Prevention of invasive fungal infections at patients (adults and children 12 years are more senior) groups of high risk, such as recipients of transplantation of haematopoietic stem cells.

Route of administration and doses:

Inside, in 1 hour prior to food or 1 hour later after food. Before therapy it is necessary to modify such electrolytic disturbances as a hypopotassemia, a hypomagnesiemia and a hypocalcemia (see also section "Side effect").

Adult patients. Therapy should be begun with intravenous administration of a vorikonazol in the recommended sating dose that in the first day to achieve adequate concentration in a blood plasma. It is necessary to continue intravenous administration at least 7 days then transition to oral administration of drug is possible provided that the patient is capable to accept medicines for intake. Considering the high bioavailability of a vorikonazol at oral administration reaching 96% (see the section "Pharmacokinetics"), in the presence of clinical indications it is possible to pass from drug, intravenous on oral administration, without dose adjustment.

Detailed information on dosing of a vorikonazol is provided in the table:

 

Selection of a dose for intake. At insufficient efficiency of treatment the maintenance dose of drug of a vorikonazol for intake can be increased from 200 mg each 12 h to 300 mg each 12 h. At patients with body weight less than 40 kg the dose can be increased from 100 mg to 150 mg each 12 h.

If the patient does not transfer drug in a high dose (that is 300 mg inside each 12 h), then a maintenance dose for intake with a step each 12 h gradually reduce 50 mg to 200 mg (for patients with body weight less than 40 kg - to 100 mg each 12 h).

Duration of treatment depends on clinical effect and results of laboratory researches.

Renal failure. 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 (ACT), 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 dose of a vorikonazol, and to reduce a maintenance dose twice. Patients with the expressed abnormal liver function (a class C on classification of Chayld-Pyyu) should appoint вориконазол 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 patients.

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

The mode of dosing of a vorikonazol at children (aged from 3 up to 12 years) and teenagers aged from 12 up to 14 years and with a body weight less than 50 kg:

Therapy is recommended to be begun with intravenous administration of a vorikonazol, and the possibility of oral administration of drug should be considered only after clinical improvement and a possibility of the patient to accept peroral medicines.

It is necessary to take into account that influence of drug at intravenous administration in a dose of 8 mg/kg is approximately twice higher, than at use inside in a dose of 9 mg/kg. 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, i.e. tablets cannot be divided. The pharmacokinetics and portability of higher doses of a vorikonazol for intake at children were not studied.

Recommendations about use of a vorikonazol inside at children are made on the basis of researches of its use in the form of powder for preparation of suspension for intake. Bioequivalence of a vorikonazol 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 3 up to 12 years with abnormal liver functions or kidneys was not studied.

At teenagers (aged from 12 up to 14 years with the body weight of 50 kg or more; from 15 to 18 years regardless of body weight) вориконазол are dosed the same as for adults.

Dose adjustment. At the inadequate clinical answer of the patient, the dose can be increased with a step of 1 mg/kg (or 50 mg if initially applied the maximum dose of 350 mg).

Features of use:

Pregnancy and 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. For the period of drug use breastfeeding should be stopped.

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

Capture of material for crops and other laboratory researches (a serology, a histopathology) for the purpose of allocation and identification of activators should be made prior to treatment. Treatment can be begun before obtaining results of laboratory researches. However after obtaining these results it is necessary to correct antifungal therapy.

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.

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. 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 infrequently observed.

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. 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 development of visual disturbances is unknown. 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) at 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.

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 (definition of activity of amylase and a lipase in blood serum) for the solution of a question of therapy vorikonazoly.

The undesirable phenomena from skin. 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.

If at the patient exfoliative skin reactions develop, then вориконазол it is necessary to cancel. As during therapy vorikonazoly development of a photosensitization is possible, during treatment patients are 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.

The undesirable phenomena from a musculoskeletal system. There are messages on cases of development of a periostitis in the patients after transplantation receiving long therapy vorikonazoly. Therapy vorikonazoly should be cancelled if the patient has an ostealgia and on the roentgenogram the changes characteristic of a periostitis are noted.

Use for children. Vorikonazol is shown for use for children aged from 3 years and is more senior at constant control of function of a liver. Bioavailability of a vorikonazol at intake at children aged from 3 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.

Narcotic analgetics of short action (CYP3A4 isoenzyme substrates). As the alfentanil elimination half-life at its simultaneous use 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.

Influence on ability to manage vehicles and mechanisms. 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 uses 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 malignant 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). Besides, safety of a vorikonazol was studied in researches with participation of the patients receiving treatment vorikonazoly with the preventive purpose. The profile of side effect of a vorikonazol in these researches was same, as in a research of 2000 patients.

The undesirable phenomena which were observed at use of a vorikonazol 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 (> 10%), frequent (> 1% and <10%), infrequent (> 0,1% and <1%), rare (> 0,01% and <ODES of %), very rare (<0,01%).

Laboratory indicators: frequent - an abnormal liver function (including increase in activity of ACT, ALT, an alkaline phosphatase, gamma glutaminetransferase, a lactate dehydrogenase, concentration of bilirubin), increase in concentration of creatinine in a blood plasma; infrequent - increase in residual nitrogen of urea, a hypercholesterolemia.

From cardiovascular system: very frequent - peripheral hypostases; frequent - a lowering of arterial pressure, thrombophlebitis, phlebitis; infrequent - fibrillation of ventricles, ventricular arrhythmia, a syncope, atrial arrhythmia, supraventricular arrhythmia, supraventricular tachycardia, bradycardia, tachycardia, lengthening of an interval of QT; rare - ventricular tachycardia on the pirouette type; total atrioventricular block, blockade of a leg of a ventriculonector, nodal arrhythmias, lymphangitis.

From system of a hemopoiesis and lymphatic system: frequent - a pancytopenia, thrombocytopenia, a leukopenia, a purpura, anemia (including, macrocytic, microcytic, normotsitarny, megaloblastny, aplastic), a marrow depression; infrequent - a syndrome of the disseminated intravascular coagulation, a lymphadenopathy, an agranulocytosis, an eosinophilia.

From a nervous system: very frequent - a headache; frequent - dizziness, confusion of consciousness, agitation, a tremor, paresthesias; infrequent - brain hypostasis, an ataxy, a diplopia, вертиго, a hypesthesia; rare - spasms, encephalopathy, a syndrome to Giyenna-Barra, extrapyramidal frustration, drowsiness during infusion, peripheral neuropathy.

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); infrequent - a papilledema, a sclerite, a blepharitis, an optic neuritis, a 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: infrequent - a gipoakuziya, a sonitus.

From respiratory system, the chest aunt and a mediastinum: frequent - a respiratory distress syndrome, a fluid lungs, breath disturbance, a stethalgia.

From digestive tract: very frequent - nausea, vomiting, diarrhea, an abdominal pain; infrequent - a lock, a duodenitis, dyspepsia, an ulitis, a glossitis, pancreatitis, a paraglossa, peritonitis; rare - disturbance of flavoring perception.

From urinogenital system: frequent - an acute renal failure, a hamaturia; infrequent - an albuminuria, nephrite; rare - a necrosis of renal tubules.

From skin and hypodermic fabrics: very frequent - rash; frequent - a face edema, a skin itch, makulopapulezny rash, makulezny rash, papular rash, a photosensitization, an alopecia, exfoliative dermatitis, a cheilitis, an erythema; infrequent - Stephens's syndrome - Johnson, a Quincke's disease, the medicinal fixed erythema, eczema, psoriasis, urticaria; rare - a diskoidny lupus erythematosus, a multiformny erythema, a toxic epidermal necrolysis, a pseudo-porphyria.

From a musculoskeletal system and connecting fabric: frequent - a dorsodynia; infrequent - arthritis; rare - a hypertension.

From endocrine system: infrequent - insufficiency of bark of adrenal glands; rare - a hyperthyroidism, a hypothyroidism.

Disturbances of metabolism and food: frequent - a hypopotassemia, a hypoglycemia.

Infections and invasions: frequent - a gastroenteritis, a grippopodobny syndrome; rare - pseudomembranous colitis.

General and local reactions: very frequent - fever; frequent - a fever, an adynamy.

From immune system: frequent - sinusitis; infrequent - allergic reactions, anaphylactoid reactions.

From gepatobiliarny system: frequent - jaundice, cholestatic jaundice; infrequent - cholecystitis, a cholelithiasis, increase in a liver, hepatitis, a liver failure; rare - a hepatic coma.

Mental disorders: frequent - hallucinations, a depression, alarm; rare - sleeplessness.

Side effect at use for children. It was established that undesirable effects at use of a vorikonazol for children aged from 3 up to 12 years 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.

If any of the undesirable reactions specified in the instruction are aggravated, or you noticed other undesirable reactions which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

Inhibitors or inductors of isoenzymes of P450 cytochrome (CYP2C19, CYP2C9 and CYP3A4) can cause, respectively, increase or decrease in concentration of a vorikonazol in a blood plasma.

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.

Contraindications:

• Hypersensitivity to a vorikonazol or any other component of drug.
• Simultaneous use with the following drugs: CYP3A4 isoenzyme substrates - терфенадин, астемизол, цизаприд, Pimozidum or quinidine; сиролимус; rifampicin, carbamazepine it is also long the operating barbiturates (phenobarbital); рифабутин; эфавиренз in high doses (400 mg and above once a day); ритонавир in high doses (400 mg and is higher than two times in days); ergot alkaloids (ergotamine, dihydroergotamine) which are CYP3A4 isoenzyme substrates; the St. John's Wort which is made a hole (the inductor of P450 cytochrome and the R-glycoprotein) (see the section "Interaction with Other Medicines").
• Children are aged younger than 3 years.
• Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

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 FROM, a cardiomyopathy, in particular with heart failure, a sinus bradycardia, existence of symptomatic arrhythmia, a concomitant use of the drugs causing lengthening of an interval of QT.
• Also it is necessary to be careful at use of a vorikonazol for patients with electrolytic disturbances, such as: hypopotassemia, hypomagnesiemia and hypocalcemia.

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:

In the dry place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 50 mg and 200 mg. On 2, 7, 10, 14 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 4, 5, 7, 8, 10 blister strip packagings together with the application instruction in a pack from a cardboard.