Авастин®

General characteristics. Structure:

Active ingredient: 100 mg or 400 mg of a bevatsizumab in 1 bottle.

Excipients: α,α-трегалозы a dihydrate, dihydrophosphate sodium monohydrate, sodium hydrophosphate anhydrous, polysorbate 20, water for injections.

The first drug which interferes with angiogenesis process, i.e. growth of network of the blood vessels delivering nutrients and oxygen to tumor fabrics and by that allows to transfer a malignant tumor from an aggressive stage to chronic.

Pharmacological properties:

Pharmacodynamics. The drug Avastin® (бевацизумаб) - the humanized recombinant giperkhimerny monoclone which selectively contacts biologically active growth factor of an endothelium of vessels (vascular endothelial growth factor - VEGF) and neutralizes it. The drug Avastin® inhibits linkng of a growth factor of an endothelium of vessels with his receptors 1 and 2 types (Flt-1, KDR) on a surface of endothelial cells that leads to decrease in vascularization and oppression of growth of a tumor.

Bevatsizumab contains completely human frame sites with the sites of a hyper chimeric antibody of a mouse defining a complementarity which contact VEGF. Bevatsizumab receive on technology of recombinant deoxyribonucleic acid (DNA) in system for the expression presented by cells of ovaries of the Chinese hamster. Bevatsizumab consists of 214 amino acids and about 149000 have molecular weight дальтон.

Introduction of a bevatsizumab leads to suppression of metastatic progressing of a disease and decrease in microvascular permeability at various tumors of the person, including cancer of a colon, a mammary gland, pancreas and prostate.

Preclinical data on safety. Cancerogenic and mutagen potential of the drug Avastin® was not studied. At introduction the animal of the drug Avastin® observed embriotoksichesky and teratogenic action. At actively growing animals with open regions of growth use of the drug Avastin® was associated with a dysplasia of a cartilaginous plate.

Pharmacokinetics. The drug Avastin® pharmacokinetics after intravenous administration (in/in) in various doses was studied (0.1-10 mg/kg every week; 3-20 mg/kg each 2 or 3 weeks; To 5 mg/kg there are each 2 weeks or to 15 mg/kg patients have each 3 weeks) with various solid tumors.

The pharmacokinetics of a bevatsizumab, as well as other antibodies, is described by two-chamber model. Distribution of the drug Avastin® is characterized by low clearance, low volume of distribution in the central camera (Vc) and a long elimination half-life that allows to achieve maintenance of necessary therapeutic concentration of drug in plasma at introduction of 1 times to 2-3 weeks.

The clearance of a bevatsizumab does not depend on age of the patient. The clearance of a bevatsizumab is 30% higher at patients with the low level of albumine and is 7% higher at patients with a big tumoral weight in comparison with patients with average values of albumine and tumoral weight.

Distribution. Vc makes 2.73 l and 3.28 l at women and men, respectively, that corresponds to the volume of distribution of immunoglobulins of a class G (IgG) and other monoclones. Distribution volume in the peripheral camera (Vp) makes 1.69 l and 2.35 l at women and men, respectively, at purpose of a bevatsizumab with other antineoplastic drugs. After dose adjustment taking into account body weight at men Vc is 20% more, than at women.

Metabolism. After single in/in introductions of a 125I-bevatsizumab its metabolic characteristics are similar to characteristics of natural IgG of a molecule which does not contact VEGF. Metabolism and removal of a bevatsizumab corresponds to metabolism and removal of endogenous IgG, i.e. is generally carried out by a proteolytic catabolism in all cells of an organism, including endothelial cells, but not through kidneys and a liver. Linkng of IgG with neonatal receptors to a kristalliziruyushchy fragment of IgG (FcRn-receptors) protects it from cellular metabolism and provides a long elimination half-life.

Removal. The pharmacokinetics of a bevatsizumab in the range of doses from 1.5 to 10 mg/kg a week has linear character.

The clearance of a bevatsizumab makes 0.188 l/days at women and men have 0.220 l/days. After dose adjustment taking into account body weight at men the clearance of a bevatsizumab is 17% more, than at women. According to two-chamber model the elimination half-life for women makes 18 days, and for men – 20 days.

Pharmacokinetics at special groups of patients. Patients of advanced age (65 years are more senior). Significant distinction of pharmacokinetics of a bevatsizumab depending on age is not revealed.

Children and teenagers. Children and teenagers have limited data of pharmacokinetics of a bevatsizumab. The available data confirm lack of a difference between the volume of distribution and clearance of a bevatsizumab at children, teenagers and adult patients with solid tumors.

Patients with a renal failure. Safety and efficiency of a bevatsizumab at patients with a renal failure was not studied since kidneys are not the main bodies of metabolism and removal of a bevatsizumab.

Patients with a liver failure. Safety and efficiency of a bevatsizumab at patients with a liver failure was not studied since the liver is not the main body of metabolism and removal of a bevatsizumab.

Indications to use:

Metastatic colorectal cancer:
· in a combination with chemotherapy on the basis of derivatives of a ftorpirimidin.
Locally recurrent or metastatic breast cancer:
· as the first line of therapy in a combination with paklitaksely.
Widespread inoperable, metastatic or recurrent not planocellular not small-celled cancer of a lung:
· as the first line of therapy in addition to chemotherapy on the basis of platinum drugs.
Widespread and/or metastatic nephrocellular cancer:
· as the first line of therapy in a combination with interferon alpha 2a.
Glioblastoma (a glioma of the IV degree of a zlokachestvennost on classification of the World Health Organization (WHO)):
· in a combination with radiation therapy and temozolomidy at patients with for the first time the diagnosed glioblastomy;
· in monotherapy or in a combination with irinotekany at a recurrence of a glioblastoma or progressing of a disease.
Epithelial cancer of an ovary, uterine tube and primary cancer of a peritoneum:
· as the first line of therapy in a combination with karboplatiny and paklitaksely at extended (IIIB, IIIC and the IV stages on classification of the International federation of obstetricians-gynecologists (FIGO)) epithelial cancer of an ovary, uterine tube and primary cancer of a peritoneum;
· in a combination with karboplatiny and gemcitabine at epithelial cancer of an ovary, uterine tube and primary cancer of a peritoneum, recurrent, sensitive to platinum drugs, at the patients who were earlier not receiving therapy bevatsizumaby or other VEGF inhibitors;
· in a combination with paklitaksely, or topotekany, or pegylated liposomal doxorubicine at epithelial cancer of an ovary, uterine tube and primary cancer of a peritoneum, recurrent, resistant to platinum drugs, at the patients who received earlier no more than two modes of chemotherapy.

Route of administration and doses:

The drug Avastin® is administered only intravenously kapelno; it is impossible to administer the drug intravenously struyno!

The drug Avastin® is not intended for intravitrealny introduction.

The drug Avastin® pharmaceutical is incompatible with dextrose solutions.

The necessary amount of the drug Avastin® is parted up to the required capacity of 0.9% with chloride sodium solution with observance of rules of an asepsis. Concentration of a bevatsizumab in the prepared solution has to be in limits of 1.4-16.5 mg/ml.

The initial dose of drug is entered within 90 minutes in the form of intravenous infusion. If the first infusion is well transferred, then the second infusion can be carried out within 60 minutes. If infusion within 60 minutes is well transferred, then all subsequent infusions can be carried out within 30 minutes.

It is not recommended to reduce a dose of a bevatsizumab because of the undesirable phenomena. In case of need, the drug Avastin® it is necessary to stop treatment completely or temporarily.

Standard mode of dosing. Metastatic colorectal cancer. As the first line of therapy: 5 mg/kg once in 2 weeks or 7.5 mg/kg once in 3 weeks in the form of intravenous infusion, are long.

It is recommended to carry out therapy by the drug Avastin® to emergence of signs of progressing of a disease or to unacceptable toxicity. As the second line of therapy: the patients who were earlier receiving therapy by the drug Avastin® after the first progressing of a disease can continue treatment by the drug Avastin® on condition of change of the mode of chemotherapy:
- when progressing a disease after therapy of the first line including the drug Avastin®: 5 mg/kg once in 2 weeks or 7.5 mg/kg once in 3 weeks in the form of intravenous infusion, are long;
- when progressing a disease after therapy of the first line which was not including the drug Avastin®: 10 mg/kg once in 2 weeks or 15 mg/kg once in 3 weeks in the form of intravenous infusion, are long.

Locally recurrent or metastatic breast cancer (BC). 10 mg/kg once in 2 weeks in the form of intravenous infusion, are long. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

Widespread inoperable, metastatic or recurrent not planocellular not small-celled cancer of a lung. The drug Avastin® is appointed in addition to chemotherapy on the basis of platinum drugs (the maximum duration of chemotherapy of 6 cycles), further administration of the drug Avastin® continues in the form of monotherapy. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

The recommended doses:
- 7.5 mg/kg once in 3 weeks in the form of intravenous infusion in addition to chemotherapy on the basis of Cisplatinum;
- 15 mg/kg once in 3 weeks in the form of intravenous infusion in addition to chemotherapy on the basis of a karboplatin.

Widespread and/or metastatic nephrocellular cancer. 10 mg/kg once in 2 weeks in the form of intravenous infusion, are long. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

Glioblastoma (a glioma of the IV degree of a zlokachestvennost according to the WHO classification). At for the first time the diagnosed disease: 10 mg/kg once in 2 weeks in the form of intravenous infusion in a combination with radiation therapy and temozolomidy, within 6 weeks. After a 4 weeks break administration of the drug Avastin® renew in a dose 10 mg/kg once in 2 weeks in a combination with temozolomidy. Temozolomid appoint 4 weeks cycles, therapy duration temozolomidy – up to 6 cycles. Further administration of the drug Avastin® continues in the form of monotherapy in a dose of 15 mg/kg once in 3 weeks.

At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped. At a recurrent disease: 10 mg/kg once in 2 weeks in the form of intravenous infusion, are long. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

Epithelial cancer of an ovary, uterine tube and primary cancer of a peritoneum. As the first line of therapy: 15 mg/kg once in 3 weeks in the form of intravenous infusion in addition to a karboplatin and a paklitaksel (the maximum duration of chemotherapy of 6 cycles), further administration of the drug Avastin® proceed in the form of monotherapy. The general duration of therapy by the drug Avastin® - 15 months. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

At a recurrent disease:
· sensitive to platinum drugs: 15 mg/kg once in 3 weeks in the form of intravenous infusion in a combination with karboplatiny and gemcitabine (6 - 10 cycles), further administration of the drug Avastin® proceed in the form of monotherapy.

At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

· resistant to platinum drugs:
10 mg/kg once in 2 weeks in the form of intravenous infusion in a combination with one of the following drugs: paklitaksely, topotekany (at the "weekly" mode of introduction of a topotekan – that is in the 1, 8 and 15 days each 4 weeks) either pegylated liposomal doxorubicine or 15 mg/kg once in 3 weeks in the form of intravenous infusion in a combination with topotekany, applied daily within 5 consecutive days each 3 weeks. At emergence of signs of progressing of a disease or unacceptable toxicity therapy by the drug Avastin® should be stopped.

The dosing mode at special groups of patients. Children and teenagers. Safety and efficiency of a bevatsizumab at children and teenagers is not established.

Patients of advanced age (65 years are more senior). Dose adjustments at patients are aged more senior than 65 years it is not required.

Patients with a renal failure. Safety and efficiency of a bevatsizumab at patients with a renal failure was not studied.

Patients with a liver failure. Safety and efficiency of a bevatsizumab at patients with a liver failure was not studied.

Features of use:

Before use solution needs to be examined regarding mechanical inclusions and discoloration.

The drug Avastin® does not contain antimicrobic preservative therefore it is necessary to provide sterility of the prepared solution and to use it immediately. If drug is not used at once, then time and storage conditions of the prepared solution are responsibility of the user. It is possible to store the prepared solution no more than 24 hours at a temperature from +2 °C to +8 °C if cultivation is carried out in controlled and validirovanny aseptic conditions. Chemical and physical stability of the prepared solution remain within 48 hours at a temperature from +2 °C to +30 °C of 0.9% chloride sodium solution. The unused drug which remained in a bottle is destroyed as it does not contain preservatives.

It is necessary to specify the trade name of drug (Авастин®) in medical documentation of the patient. Replacement of drug by any other biological medicine demands approval of the attending physician. Information provided in this instruction belongs only to the drug Avastin®.

Treatment by the drug Avastin® can be carried out only under observation of the doctor having experience of use of antineoplastic therapy. The patients receiving the drug Avastin® have an increased risk of development of perforation of the digestive tract (DT) and gall bladder. Hard cases of perforation of a GIT including fatal were observed (at 0.2%-1% of all patients receiving the drug Avastin®). The clinical picture a perforatsy GIT differed on weight and varied depending on signs of free gas at a X-ray analysis of an abdominal cavity which disappeared without treatment, to perforation with abscess of an abdominal cavity and a lethal outcome. In certain cases the initial intraperitoneal inflammation as a result of a peptic ulcer of the stomach, a necrosis of a tumor, a diverticulitis or colitis associated with chemotherapy took place. Communication between development of an intraperitoneal inflammation and a perforatsy GIT and therapy by the drug Avastin® is not established. At development of perforation of a GIT treatment by the drug Avastin® should be stopped.

At therapy the drug Avastin® registered serious cases of formation of fistulas, including cases with a lethal outcome. GIT fistulas most often arose at patients with a metastatic colorectal cancer and cancer of an ovary (to 2% of patients), is more rare at other localizations of a tumor. Infrequently (≥0.1% - <1%) cases of formation of fistulas of other localizations were registered (bronchopleural, urogenital, biliary). Formation of fistulas is more often observed in the first 6 months of therapy by the drug Avastin®, but can arise both in 1 week, and in 1 year and later after the beginning of therapy.

When developing tracheooesophageal fistula or fistula of any localization 4 severity therapy by the drug Avastin® should be cancelled. There are limited data on continuation of use of the drug Avastin® at patients with fistulas of other localizations. When developing the internal fistula which is not getting into a GIT it is necessary to consider a question of drug withdrawal of Avastin®.

At the patients receiving the drug Avastin® the risk of developing of bleedings, especially bleedings from a tumor is increased. The drug Avastin® it is necessary to cancel when developing bleeding 3 or 4 severity on NCI-CTC classification. The general frequency of developing of bleedings 3-5 severity at use of the drug Avastin® according to all indications makes 0.4%-6.5%. Bleedings from a tumor or small bleedings were most often observed from a mucous membrane and skin (for example, nasal bleeding).

Nasal bleedings of 1 severity on NCI-CTC classifications lasting less than 5 minutes, allowed without medical intervention and not demanding change of the mode of a drug dosing of Avastin® were most often observed. Frequency of small bleedings from a mucous membrane and skin depends on a drug dose. There were small bleeding of gums or vaginal bleedings less often.

Plentiful or massive pulmonary bleedings / a pneumorrhagia were observed generally at not small-celled cancer of a lung. Reception of antirheumatic / antiinflammatory drugs, anticoagulants, the previous radiation therapy, atherosclerosis, the central arrangement of a tumor, formation of a cavity to or during treatment are possible risk factors of development of pulmonary bleedings / pneumorrhagias, at the same time only for planocellular cancer of a lung statistically reliable connection with development of bleedings is established.

The patients who recently had a bleeding/pneumorrhagia (more than 2.5 ml of blood) should not receive the drug Avastin®.

At patients with a colorectal cancer the GIT bleedings connected with a tumor including rectal bleeding and a melena are possible.

Bleedings, including intracraneal hemorrhages, at patients with metastatic damage of the central nervous system (CNS) or from glioblastomy were seldom observed.

It is necessary to carry out monitoring of symptoms of intracraneal hemorrhages, in case of their emergence to cancel therapy by the drug Avastin®.

At patients with inborn hemorrhagic diathesis, the acquired coagulopathy or the anticoagulants receiving a full dose concerning a thromboembolism, before purpose of the drug Avastin® it is necessary to be careful in view of lack of information on a profile of safety of drug at such patients. Increase in frequency of development of bleeding 3 severity above at the patients receiving the drug Avastin® and warfarin was not observed.

Separate cases, and also series of cases of the serious undesirable phenomena from an organ of sight were reported (including an infectious entophthalmia and other inflammatory diseases) after the unregistered intravitrealny administration of the drug Avastin®. Some of these phenomena led to loss of visual acuity of varying severity, including a persistent blindness. The drug Avastin® is not intended for intravitrealny introduction.

At the patients receiving the drug Avastin® the increased frequency of developing of arterial hypertension of all severity was observed (to 42.1%). According to all indications the frequency of arterial hypertension 3-4 severity on classification of NCI-CTC made 0.4%-17.9%; 4 severity (hypertensive crisis) it was observed at 1% of patients.

Clinical data on safety allow to assume that the frequency of cases of increase in the arterial pressure (AP) probably depends on a dose of a bevatsizumab.

The drug Avastin® can be appointed only by the patient with previously compensated arterial hypertension with further control of the ABP. Information on influence of the drug Avastin® at patients with uncontrollable arterial hypertension at the time of the beginning of therapy is absent. At patients with the arterial hypertension demanding medicinal therapy it is recommended to stop temporarily therapy by the drug Avastin® before achievement of normalization of the ABP.

In most cases normalization of the ABP is reached by means of standard anti-hypertensive means (inhibitors of an angiotensin-converting enzyme (APF), diuretics and blockers of the "slow" calcium channels) chosen individually for each patient. Therapy cancellation the drug Avastin® or hospitalization required seldom.

Cases of hypertensive encephalopathy, some with a lethal outcome were very seldom observed. The risk of developing of the arterial hypertension associated with therapy by the drug Avastin® does not correlate with initial characteristics of the patient, an associated disease or the accompanying therapy.

Therapy by the drug Avastin® needs to be stopped in the absence of normalization of the ABP, development of hypertensive crisis or hypertensive encephalopathy.

At therapy the drug Avastin® registered isolated cases of the syndrome of back reversible encephalopathy which is shown an epileptic seizure, a headache, mental disturbances, a vision disorder, defeat of the visual centers of a cerebral cortex with or without arterial hypertension and other symptoms. The diagnosis can be confirmed by means of methods of visualization of a brain (preferably by means of the magnetic and resonant tomography (MRT)). In case of development of a syndrome of back reversible encephalopathy it is necessary to appoint symptomatic therapy, to carefully control the ABP and to cancel the drug Avastin®. Usually permission or improvement of symptomatology comes in several days, however at some patients neurologic complications were observed. Safety of repeated purpose of the drug Avastin® at such patients is not established.

At therapy by the drug Avastin® in a combination with chemotherapy the frequency of an arterial thromboembolism, including a stroke, the tranzitorny ischemic attack and a myocardial infarction and other phenomena of an arterial thromboembolism was higher, than at appointment only chemotherapy. The general frequency of emergence of cases of an arterial thromboembolism made 5%. When developing an arterial thrombembolia therapy by the drug Avastin® needs to be stopped. The arterial thromboembolism in the anamnesis, a diabetes mellitus or age is more senior than 65 years are associated with the increased risk of developing of an arterial thrombembolia during treatment by the drug Avastin®. At treatment of such patients it is necessary to show care.

During treatment the increased risk of development of a venous thromboembolism (TELA, a deep vein thrombosis, thrombophlebitis) is available the drug Avastin®. The general frequency of developing of a venous thrombembolia (a deep vein thrombosis and TELA) varies from 2.8% to 17.3%.

Therapy by the drug Avastin® needs to be stopped at emergence of the zhizneugrozhayushchy phenomenon (the 4th severity) of a venous thromboembolism, including TELA, and at severity of a venous thromboembolism ≤3 it is necessary to carry out careful monitoring of a condition of the patient.

The Chronic Heart Failure (CHF) arose at use of the drug Avastin® according to all indications, but generally at a metastatic breast cancer.

Were observed as asymptomatic decrease in fraction of emission of a left ventricle, and HSN which demanded therapy or hospitalization.

HSN 3 severity was observed at 3.5% of the patients receiving the drug Avastin® above. At the patients receiving the drug Avastin® in a combination with drugs of an anthracycline row HSN frequency 3 severity did not differ from the available data above at therapy of a metastatic breast cancer. At most of patients improvement of symptoms and/or fractions of emission of a left ventricle was observed at the corresponding treatment.

Data on risk of development of HSN in patients with class HSN II-IV on classification of the New York association of cardiologists (NYHA) in the anamnesis are absent.

In most cases HSN arose at the patients with a metastatic breast cancer receiving therapy by anthracyclines, radiation therapy on area of a thorax in the anamnesis or with other risk factors of development of HSN.

It is necessary to show care at purpose of the drug Avastin® to patients with clinically significant cardiovascular disease in the anamnesis, such as coronary heart disease or HSN.

At patients who did not receive therapy by drugs of an anthracycline row earlier at use of the drug Avastin® and drugs of an anthracycline row increase in frequency of HSN of any severity in comparison with monotherapy by drugs of an anthracycline row was not observed. HSN 3 severity arose slightly more often in group of therapy by the drug Avastin® in a combination with chemotherapy in comparison with only chemotherapy above that corresponds also to other data obtained at patients with a metastatic breast cancer and not receiving the accompanying therapy by anthracyclines.

At patients with a diffusion V-macrocellular lymphoma at therapy bevatsizumaby and doxorubicine in a cumulative dose more than 300 mg/sq.m were observed increase in number of new cases of HSN. When comparing therapy of ритуксимаб/циклофосфамид/доксорубицин/винкристин/преднизолон (R-CHOP) + бевацизумаб and R-CHOP the number of new cases did not differ, but it was higher, than observed earlier at therapy by doxorubicine. Frequency of HSN was higher in the R-CHOP group + бевацизумаб.

The drug Avastin® can negatively influence healing of wounds. Bevatsizumaby it is necessary to begin treatment not less than in 28 days after extensive surgical intervention or at full healing of a surgical wound. At development during treatment of the complications connected with a wound repair, the drug Avastin® needs to be cancelled temporarily to a full wound repair. Administration of the drug Avastin® needs also to be stopped temporarily in case of carrying out planned surgical intervention.

Exceptional cases of a necrotizing fasciitis (including with a lethal outcome) at the patients receiving treatment by the drug Avastin® are registered. This phenomenon, as a rule, developed against the background of disturbance of healing of wounds, perforation of digestive tract or formation of fistulas.

In case of identification of a necrotizing fasciitis the drug Avastin® has to be the corresponding treatment is cancelled and is immediately begun.

The proteinuria was observed at 0.7%-38% of the patients receiving the drug Avastin®. On severity the proteinuria varied from tranzitorny asymptomatic identification of traces of protein in urine and at 1.4% of patients to a nephrotic syndrome (a proteinuria 4 severity). The proteinuria 3 severity is registered at 8.1% of the patients receiving the drug Avastin® according to various indications. The proteinuria was not associated with a renal failure and seldom demanded therapy cancellation by the drug Avastin®.

The risk of development of a proteinuria is increased at patients with arterial hypertension in the anamnesis. Perhaps, the proteinuria of 1 degree depends on a drug Avastin® dose.

At development of a proteinuria 4 degrees the drug Avastin® need to be cancelled. Prior to the beginning of and during therapy the drug Avastin® recommends to carry out the analysis of urine on a proteinuria.

In most cases at a proteinuria of ≥2 g a day therapy by the drug Avastin® temporarily stopped before decrease in a proteinuria <2 g a day.

At therapy the drug Avastin® in a combination with the miyelotoksichny modes of chemotherapy observed increase in frequency of development of a heavy neutropenia, febrile neutropenia or infections with a heavy neutropenia (including cases with a lethal outcome).

At patients the increased risk of development of infusional reactions / reactions of hypersensitivity can be observed. There are data on more frequent development of anaphylactic reactions and reactions of anaphylactoid type at the patients receiving the drug Avastin® in a combination with chemotherapy in comparison with the patients receiving only chemotherapy.

Careful observation of the patient in time and after administration of the drug Avastin® is recommended. At emergence of infusional reaction it is necessary to interrupt infusion and to hold the relevant medical activities. Systematic premedication cannot be a guarantee of lack of infusional reactions / reactions of hypersensitivity.

Jaw osteonecrosis. It was reported about jaw osteonecrosis cases at the oncological patients receiving the drug Avastin®. Most of these patients received bisfosfonata intravenously earlier or as the accompanying therapy; the osteonecrosis of a jaw is the identified risk for bisfosfonat.

It is necessary to be careful at simultaneous or consecutive use of the drug Avastin® and bisfosfonat intravenously. Invasive dental procedures are also the identified risk factor. Prior to treatment by the drug Avastin® it is necessary to conduct dental examination and the relevant preventive dental activities. Whenever possible it is necessary to avoid holding invasive dental procedures at the patients who were earlier receiving or receiving now bisfosfonata intravenously.

Patients are more senior than 65 years: at purpose of the drug Avastin® to patients 65 years are more senior there is an increased risk of developing of an arterial thrombembolia (including development of a stroke, the tranzitorny ischemic attack, a myocardial infarction), leukopenias 3-4 severity and thrombocytopenia, and also a neutropenia (all severity), diarrhea, nausea, a headache and fatigue in comparison with patients of ≤65 years. Increases in frequency of development of other side reactions connected using the drug Avastin® (perforation of a GIT, the complications connected with healing of wounds, arterial hypertension, a proteinuria, HSN and bleedings), at patients are more senior than 65 years in comparison with patients of ≤65 years it is noted.
 
Men and women of childbearing age during treatment by the drug Avastin® and, at least, within 6 months after the end of treatment need to use reliable methods of contraception.

The drug Avastin® can break fertility at women. At most of patients fertility was recovered after the therapy termination by the drug Avastin®. The remote effects of therapy by the drug Avastin® on fertility are unknown.

Feeding by breast milk is not recommended during treatment by the drug Avastin® and, at least, within 6 months after the end of therapy by the drug Avastin®.

Utilization of unused drug or expired has to be carried out according to requirements of medical institution.
 
Influence on ability to manage vehicles and mechanisms. Researches on studying of influence of drug on ability to manage vehicles, were not conducted by mechanisms. To patients who had such undesirable phenomena as to a syncope drowsiness or a vision disorder, it is necessary to refrain from control of vehicles, mechanisms.

Side effects:

The most serious side effects: perforation of digestive tract, hemorrhage, including pulmonary bleedings / a pneumorrhagia (meet at patients with not small-celled cancer of a lung more often), an arterial thromboembolism.

At the patients receiving the drug Avastin® were most often observed: increase in arterial pressure, weakness or adynamy, diarrhea and abdominal pain.

Increase in arterial pressure and development of a proteinuria probably has dozozavisimy character.

Side reactions of all severity on the classifications of National institute of cancer (NCI-CTC) which were found at the patients receiving the drug Avastin® in a combination with various chemotherapeutic modes according to all indications are given below. For the description of frequency of side reactions the following categories are used: very often (³10%), it is frequent (³1% - <10%), infrequently (≥ 0.1% - <1%), is rare (≥ 0.01% - <0.1%) and is very rare (<0.01%).

Undesirable reactions are referred to a certain category according to the largest frequency of emergence. Within one category of frequency undesirable reactions are presented as decrease in gravity. Some of the listed undesirable reactions often are observed at chemotherapy (for example, a palmar and bottom syndrome at therapy kapetsitabiny and peripheral touch neuropathy at therapy paklitaksely or oksaliplatiny); however it is impossible to exclude weighting of a state at therapy by the drug Avastin®. At use of the drug Avastin® in a combination with pegylated liposomal doxorubicine increase in risk of development of a palmar and bottom syndrome is possible.

From system of a hemopoiesis: very often – a febrile neutropenia, a leukopenia, a neutropenia, thrombocytopenia; often – anemia.

From a nervous system: very often – peripheral touch neuropathy, a dysgeusia, a headache, a dysarthtia; often – a stroke, a syncope, drowsiness.

From an organ of sight: very often – a vision disorder, the raised dacryagogue.

From cardiovascular system: very often – increase in arterial pressure; often – chronic heart failure, supraventricular tachycardia, an arterial thromboembolism, a deep vein thrombosis, bleeding, including pulmonary, intracranial, from a mucous membrane and skin, a GIT and from a tumor.

From a respiratory organs: very often – short wind, nasal bleeding, rhinitis; often – a thromboembolism of a pulmonary artery (TELA), a hypoxia.

From digestive tract: very often – anorexia, diarrhea, nausea, vomiting, a lock, stomatitis, rectal bleeding; often – perforation of digestive tract, impassability of intestines, including obturatsionny, an abdominal pain, gastrointestinal frustration.

From reproductive system: very often – insufficiency of function of ovaries (an amenorrhea lasting 3 months and more (concentration of follicle-stimulating hormone (FSG) 30mme/ml at the negative test for pregnancy with definition a beta of a chorionic gonadotrophin of the person (β-HGCh) in serum).

From skin and a hypodermic fatty tissue: very often – exfoliative dermatitis, a xeroderma, skin discoloration; often – a palmar and bottom syndrome.

From a musculoskeletal system: very often – an arthralgia; often – muscular weakness, a mialgiya.

From an urinary system: very often – a proteinuria; often – an infection of urinary tract.

Local reactions: very often – pains, including in a drug injection site.

Others: very often - an adynamy, the increased fatigue, a pyrexia, an inflammation of mucous membranes of various localization; often – a lethargy, block, sepsis, abscess, accession of consecutive infections, dehydration.

Disturbances from laboratory indicators: hyperglycemia, hypopotassemia, hyponatremia, increase in a prothrombin time, increase in the international normalized relation (INR)

Post-marketing observation.
From a nervous system: hypertensive encephalopathy (very seldom); syndrome of back reversible encephalopathy (seldom).

From cardiovascular system: the trombotichesky mikroangiopatiya of kidneys which is clinically shown a proteinuria (frequency of emergence is unknown).

From a respiratory organs: perforation of a nasal partition (frequency of emergence is unknown), pulmonary hypertensia (frequency of emergence is unknown), a dysphonia (often).

From digestive tract: a gastrointestinal ulcer (frequency of emergence is unknown).

From a liver and biliary tract: perforation of a gall bladder (frequency of emergence is unknown).

Allergic and infusional reactions: hypersensitivity reactions, infusional reactions (frequency of emergence is unknown); with the following possible simultaneous manifestations: breath asthma/difficulty, "inflows"/reddening/rash, decrease or increase in arterial pressure, decrease in saturation by oxygen, stethalgia, fever and nausea/vomiting.

From a musculoskeletal system: a jaw osteonecrosis (generally at the patients who were receiving the accompanying therapy of a bisfosfonatama or receiving therapy of a bisfosfonatama earlier).

Others: a necrotizing fasciitis, as a rule, against the background of disturbance of healing of wounds, perforation of digestive tract or formation of a fistula (seldom).

Interaction with other medicines:

Influence of antineoplastic drugs on drug Avastin® pharmacokinetics. Clinically significant influence on drug Avastin® pharmacokinetics at use, joint with chemotherapy, was not registered. It is not revealed statistically or clinically significant distinctions of clearance of the drug Avastin® at the patients receiving monotherapy and at the patients receiving the drug Avastin® in a combination with interferon alpha 2а or other chemotherapeutic drugs (IFL, FU/LV, karboplatin/paklitakset, капецитабин, doxorubicine or Cisplatinum/gemcitabine).

Influence of the drug Avastin® on pharmacokinetics of other antineoplastic drugs. The drug Avastin® does not exert considerable impact on pharmacokinetics of an irinotekan and its active metabolite (SN38); a kapetsitabin and its metabolites, and also an oksaliplatin (was determined by the free and general level of platinum); interferon alpha 2а; Cisplatinum.
There are no reliable data about influence of the drug Avastin® on pharmacokinetics of gemcitabine.

Combination of the drug Avastin® and sunitinib. At drug Avastin® use (10 mg/kg once in 2 weeks) in a combination with sunitiniby (50 mg daily) at patients with metastatic nephrocellular cancer cases of development of mikroangiopatichesky hemolitic anemia (MAGICIAN) are registered. The MAGICIAN treats subgroup of hemolitic anemias which can be shown by fragmentation of erythrocytes, anemia and thrombocytopenia. At some patients neurologic disturbances, increase in concentration of creatinine, arterial hypertension, including hypertensive crisis are in addition noted. These symptoms were reversible after the therapy termination bevatsizumaby and sunitiniby.

Radiation therapy. At use of the drug Avastin® in a combination with radiation therapy and chemotherapy (temozolomidy) at patients with for the first time remains diagnosed glioblastomy a profile of safety of drug invariable.

Safety and efficiency of the drug Avastin® in a combination with radiation therapy at other indications is not established.

The drug Avastin® pharmaceutical is incompatible with dextrose solutions.

Contraindications:

Hypersensitivity to a bevatsizumab or to any other component of drug, drugs on the basis of cells of ovaries of the Chinese hamster or to others recombinant human or approximate to human antibodies. Pregnancy and period of feeding by a breast. Children's age up to 18 years, a renal and liver failure (efficiency and safety of use are not established).
 
With care. At an arterial thromboembolism in the anamnesis; diabetes mellitus; age 65 years are more senior; inborn hemorrhagic diathesis and the acquired coagulopathy; at reception of anticoagulants for treatment of a thromboembolism prior to therapy by the drug Avastin®; clinically significant cardiovascular disease (coronary heart disease or chronic heart failure in the anamnesis); arterial hypertension; venous thromboembolism; healing of wounds; bleeding/pneumorrhagia; gastrointestinal perforation in the anamnesis; syndrome of back reversible encephalopathy; neutropenias; proteinurias.

Overdose:

At purpose of a bevatsizumab in the maximum dose of 20 mg/kg each 2 weeks intravenously at several patients the headache (migraine) of heavy severity is noted.

At overdose strengthening of above-mentioned dozozavisimy by-effects is possible. There is no specific antidote. Symptomatic treatment.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging.

To store at a temperature of 2-8 °C in the place protected from light. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 100 mg / 4 ml and 400 mg / 16 ml. On 100 mg / 4 ml or 400 mg / 16 drug ml in the glass bottle (glass of hydrolytic class I EF) corked by a stopper from the butyl rubber laminated by a ftorpolimer, which is pressed out by an aluminum cap and closed by a plastic cover. 1 bottle together with the application instruction is placed in a cardboard pack.

Packaging on CJSC ORTAT: 1 bottle with drug is placed in the plastic or cardboard pallet which together with the application instruction place in a pack from a cardboard for a retail container of subgroups chrome-ersatz in accordance with GOST 7933-89 or import. For the purpose of control of the first opening on a pack paste self-adhesive round stickers with a logo of CJSC ORTAT.