Avastin® (Avastin®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceBevacizumabBevacizumab
Similar drugsTo uncover
  • Avastin®
    solution in / in 
    Hoffmann-La Roche Ltd.     Switzerland
  • Avegra® BIOCAD
    concentrate d / infusion 
    BIOCAD, CJSC     Russia
    • Dosage form: & nbsp

    concentrate for solution for infusion

    Composition:

    1 bottle contains:

    active substance: bevacizumab - 100 mg (concentration in vial 100 mg / 4 ml) / 400 mg (concentration in vial 400 mg / 16 ml);

    Excipients: α,α- trehalose dihydrate - 240.0 / 960.0 mg, sodium dihydrogen phosphate monohydrate - 23.2 / 92.8 mg, sodium hydrophosphate anhydrous -4.8 / 19.2 mg, polysorbate 20 - 1.6 / 6.4 mg, water for injection up to 4.0 / 16.0 ml.

    Description:Transparent or opalescent liquid, colorless or light brown in color.
    Pharmacotherapeutic group:Antineoplastic agent, monoclonal antibodies
    ATX: & nbsp

    L.01.X   Other antineoplastic agents

    Pharmacodynamics:

    Avastin® preparation (bevacizumab) is a humanized recombinant hyperchimeric monoclonal antibody that selectively binds to a biologically active vascular endothelial growth factorvascular endothelial growth factor - VEGF) and neutralizes it. Avastin® inhibits the binding of the vascular endothelial growth factor to its type 1 and 2 receptors (Flt-1, KDR) on the surface of endothelial cells, which leads to a reduction in vascularization and inhibition of tumor growth.

    Bevacizumab contains fully human framework regions with complementarity determining regions of the hyperchimeric mouse antibody that bind to VEGF. Bevacizumab are obtained by recombinant deoxyribonucleic acid (DNA) technology in a system for expression represented by Chinese hamster ovary cells. Bevacizumab consists of 214 amino acids and has a molecular weight of about 149,000 daltons.

    The introduction of bevacizumab leads to suppression of metastatic progression of the disease and a decrease in microvascular permeability in various human tumors, including colon, breast, pancreas and prostate cancer.

    Preclinical safety data

    The carcinogenic and mutagenic potential of Avastin® has not been studied.

    When Avastin® was administered to animals, embryotoxic and teratogenic effects were observed.

    In actively growing animals with open growth zones, Avastin® was associated with dysplasia of the cartilaginous plate.

    Pharmacokinetics:

    The pharmacokinetics of Avastin® was studied after intravenous administration (iv) in various doses (0.1-10 mg / kgevery week; 3-20 mg / kg every 2 or 3 weeks; 5 mg / kg every 2 weeks or 15 mg / kg every 3 weeks) in patients with various solid tumors.

    The pharmacokinetics of bevacizumab, like other antibodies, is described by a two-compartment model. Avastin® distribution is characterized by low clearance, low volume distribution in the central chamber (Vc) and a long half-life, which allows you to achieve the necessary therapeutic concentration of the drug in the plasma when administered once every 2-3 weeks.

    The clearance of bevacizumab does not depend on the age of the patient.

    Bevacizumab clearance is 30% higher in patients with low albumin levels and 7% higher in patients with a large tumor mass compared to patients with average albumin and tumor mass.

    Distribution

    Vc is 2.73 liters and 3.28 liters in women and men, respectively, which corresponds to the distribution of immunoglobulins class G (IgG) and other monoclonal antibodies. The volume of distribution in the peripheral chamber (Vp) is 1.69 liters and 2.35 liters in women and men, respectively, with the appointment of bevacizumab with other antitumor drugs. After correction of the dose taking into account the body weight in men Vc 20% more than in women.

    Metabolism

    After a single IV injection 125I-Bevasizumab its metabolic characteristics are similar to those of natural IgG molecule, which does not bind to VEGF. Metabolism and excretion of bevacizumab correspond to metabolism and elimination of endogenous IgGi.e. mainly carried out by proteolytic catabolism in all cells of the body, including endothelial cells, and not through the kidneys and liver. Binding IgG with neonatal receptors to the crystallizing fragment IgG (FcRn- receptors) protects it from cellular metabolism and provides a long half-life.

    Excretion

    The pharmacokinetics of bevacizumab in a dose range of 1.5 to 10 mg / kg per week is linear.

    The clearance of bevacizumab is 0.188 l / day in women and 0.220 l / day in men.

    After correction of the dose, taking into account the body weight in men, the clearance of bevacizumab is 17% higher than that of women. According to the two-chamber model, the elimination half-life for women is 18 days, and for men - 20 days.

    Pharmacokinetics in specific patient groups

    Patients of advanced age (over 65 years)

    There was no significant difference in the pharmacokinetics of bevacizumab, depending on age.

    Children and teens

    There are limited data on the pharmacokinetics of bevacizumab in children and adolescents. The available data indicate that there is no difference between the distribution and clearance of bevacizumab in children, adolescents and adult patients with solid tumors.

    Patients with renal insufficiency

    The safety and efficacy of bevacizumab in patients with renal insufficiency has not been studied, kidneys are not the main organs of metabolism and excretion of bevacizumab.

    Patients with hepatic insufficiency

    The safety and efficacy of bevacizumab in patients with hepatic impairment have not been studied since The liver is not the main organ of metabolism and excretion of bevacizumab.

    Indications:

    Metastatic colorectal cancer:

    - in combination with chemotherapy based on fluoropyrimidine derivatives.

    Locally recurrent or metastatic breast cancer:

    - as the first line of therapy in combination with paclitaxel.

    Common inoperable, metastatic or recurrent non-cell lung non-small cell lung cancer:

    - as a first-line therapy in addition to chemotherapy based on platinum drugs.

    Common and / or metastatic renal cell carcinoma:

    - as the first line of therapy in combination with interferon alpha-2a

    Glioblastoma (glioma of the 4th degree of malignancy according to the classification of the World Health Organization (WHO)):

    - in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma;

    - in monotherapy or in combination with irinotecan with relapse of glioblastoma or progression of the disease.

    Epithelial cancer of the ovary, uterine tube and primary cancer of the peritoneum:

    epithelial ovarian cancer, uterine tube and primary peritoneal cancer as the first line of therapy in combination with carboplatin and paclitaxel in case of widespread epithelial cancer of the ovary, SB and AL and IV stage according to the classification of the International Federation of Obstetricians and Gynecologists (FIGO);

    - in combination with carboplatin and gemcitabine with relapsing, platinum-sensitive epithelial ovarian cancer, fallopian tube and primary peritoneal cancer in patients who have not previously been treated with bevacizumab or other VEGF inhibitors;

    - in combination with paclitaxel, or topotecan, or pegylated liposomal doxorubicin in relapsing,resistant to platinum preparations epithelial ovarian cancer, uterine tube and primary peritoneal cancer in patients who received no more than two regimens of chemotherapy.

    Contraindications:

    Hypersensitivity to bevacizumab or to any other component of the drug, preparations based on Chinese hamster ovary cells or to other recombinant human or approximate human antibodies.

    Pregnancy and lactation.

    Children under 18 years of age, renal and hepatic insufficiency (efficacy and safety of use not established).

    Carefully:

    With arterial thromboembolism in history; diabetes mellitus; age over 65; congenital hemorrhagic diathesis and acquired coagulopathy; when taking anticoagulants for the treatment of thromboembolism before initiating Avastin® therapy; clinically significant cardiovascular disease (ischemic heart disease or chronic heart failure in history); arterial hypertension; venous thromboembolism; wound healing; bleeding / hemoptysis; gastrointestinal perforation in the anamnesis; syndrome of posterior reversible encephalopathy; neutropenia; proteinuria.

    Dosing and Administration:

    Avastin® injected only intravenously drip; You can not inject the drug intravenously!

    Avastin® is not intended for intravitreal administration. Avastin® is pharmaceutically incompatible with dextrose solutions. The required amount of Avastin® is diluted to the required volume with 0.9% sodium chloride solution in accordance with aseptic rules. The concentration of bevacizumab in the prepared solution should be in the range of 1.4-16.5 mg / ml. The initial dose of the drug is administered for 90 minutes in the form of intravenous infusion. If the first infusion is well tolerated, then the second infusion can be performed within 60 minutes. If the infusion is well tolerated within 60 minutes, all subsequent infusions can be carried out within 30 minutes. It is not recommended to reduce the dose of bevacizumab because of undesirable phenomena. If necessary, Avastin® should be completely or temporarily discontinued.

    Standard dosing regimen.

    Metastatic colorectal cancer.

    AT as the first line of therapy: 5 mg / kg once every 2 weeks or 7.5 mg / kg once every 3 weeks as an intravenous infusion, long-term.

    It is recommended that Avastin® treatment be given before signs of disease progression or to unacceptable toxicity.

    AT quality of the second line of therapy: Patients previously treated with Avastin® can, after the first progression of the disease, continue Avastin® treatment if the chemotherapy regimen is changed:

    - with the progression of the disease after first-line therapy, including Avastin®: 5 mg / kg once every 2 weeks or 7.5 mg / kg once every 3 weeks as an intravenous infusion, long-term;

    - with progression of the disease after first-line therapy that did not include Avastin®: 10 mg / kg once every 2 weeks or 15 mg / kg once every 3 weeks as an intravenous infusion, long-term.

    Locally recurrent or metastaticBreast Cancer (BC)

    10 mg / kg once every 2 weeks as an intravenous infusion, prolonged.

    If signs of disease progression or unacceptable toxicity appear, Avastin®to steal.

    Common inoperable, metastatic or re-iiviruyuschy neplascocellular non-small cell lung cancer.

    Avastin® is prescribed in addition to platinum-based chemotherapy (the maximum duration of chemotherapy is 6 cycles), then Avastin® continues as a monotherapy. If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued. Recommended doses:

    - 7.5 mg / kg once every 3 weeks as an intravenous infusion in addition to cisplatin-based chemotherapy;

    - 15 mg / kg once every 3 weeks as an intravenous infusion in addition to carboplatin-based chemotherapy. Common and / or metastatic Renal cell cancer 10 mg / kg once every 2 weeks as an intravenous infusion, long-term.

    If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued.

    Glioblastoma (glioma IV degree of malignancy according to WHO classification).

    With a newly diagnosed disease: 10 mg / kg once every 2 weeks as an intravenous infusion in combination with radiotherapy and temozolomide for 6 weeks.After a 4-week break, the administration of Avastin® is resumed at a dose of 10 mg / kg every 2 weeks in combination with temozolomide. Temozolomide appoint 4-week cycles, duration of therapy with temozolomide - up to 6 cycles.

    Further, Avastin® is continued as monotherapy at a dose of 15 mg / kg once every 3 weeks.

    If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued.

    With a recurrent disease: 10 mg / kg once every 2 weeks as an intravenous infusion, prolonged.

    If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued.

    Epithelial cancer of the ovary, fallopian tube and primary cancer of the peritoneum.

    As the first line of therapy: 15 mg / kg once every 3 weeks as an intravenous infusion in addition to carboplatin and paclitaxel (the maximum duration of chemotherapy is 6 cycles), then Avastin® continues as a monotherapy. The total duration of Avastin® therapy is 15 months.

    If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued.

    With a recurrent disease:

    - sensitive to platinum: 15 mg / kg once every 3 weeks as an intravenous infusion in combination with carboplatin and gemcitabine (6-10 cycles), then Avastin® continues as a monotherapy.

    If there is evidence of disease progression or unacceptable toxicity, Avastin® should be discontinued.

    - resistant to platinum: 10 mg / kg once every 2 weeks in the form of an intravenous infusion in combination with one of the following drugs: paclitaxel, topotecan (in the "weekly" topotecan administration mode - that is, on days 1, 8 and 15 every 4 weeks) or pegylated Liposomal doxorubicin or 15 mg / kg once every 3 weeks as an intravenous infusion in combination with topotecan, applied daily for 5 consecutive days every 3 weeks.

    If signs of disease progression or unacceptable toxicity appear, Avastin® treatment should be discontinued.

    Dosage regimen in specific patient groups.

    Children and teenagers.

    Safety and efficacy of bevacizumab in children and adolescents is not established.

    Patients of advanced age (over 65 years).

    Dose adjustments in patients over the age of 65 years are not required.

    Patients with renal insufficiency.

    The safety and efficacy of bevacizumab in patients with renal insufficiency has not been studied.

    Patients with hepatic insufficiency.

    The safety and efficacy of bevacizumab in patients with hepatic insufficiency has not been studied.

    Instructions for use, handling and destruction.

    Before use, the solution should be inspected for mechanical inclusions and discoloration.

    Avastin® does not contain an antimicrobial preservative, so it is necessary to ensure the sterility of the prepared solution and use it immediately. If the preparation is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user. The prepared solution can be stored for no more than 24 hours at a temperature of + 2 ° C to + 8 ° C if dilution is carried out in controlled and validated aseptic conditions.The chemical and physical stability of the prepared solution is maintained for 48 hours at a temperature of + 2 ° C to + 30 ° C in a 0.9% solution of sodium chloride. The unused drug remaining in the vial is destroyed, since it contains no preservatives.

    Side effects:The most serious side effects are gastrointestinal perforation, hemorrhage, including pulmonary hemorrhage / hemoptysis (more common in patients with non-small cell lung cancer), arterial thromboembolism.

    In patients receiving Avastin®, the most frequently observed: increased blood pressure, weakness or asthenia, diarrhea and abdominal pain. The increase in blood pressure and the development of proteinuria probably has a dose-dependent character.

    The following are the adverse reactions of all degrees of severity according to the classification National Cancer Institute (NCI-CTC), occurring in patients who received Avastin® in combination with various chemotherapeutic regimens for all indications. To describe the frequency of adverse reactions, the following categories are used: very often (>10%), often (>1% - <10%), infrequently (> 0.1% - <1%), rarely (> 0.01% - <0.1%) and very rarely (<0.01%).

    Undesirable reactions are assigned to a specific category according to the highest frequency of occurrence. Within the same frequency category, unwanted reactions are presented in order of severity. Some of these unwanted reactions are often observed with chemotherapy (for example, palmar dyspnea syndrome with capecitabine therapy and peripheral sensory neuropathy with paclitaxel or oxaliplatin); However, we can not rule out the weighting of the condition with Avastin® therapy. When Avastin® is used in combination with pegylated liposomal doxorubicin, an increased risk of developing the palmar dysbolism syndrome is possible.
    On the part of the hematopoiesis system: very often - febrile neutropenia, leukopenia, neutropenia, thrombocytopenia; often anemia.
    From the nervous system: very often - peripheral sensory neuropathy, dysgeusia, headache, dysarthria; often - stroke, syncope, drowsiness.
    From the side of the organ of vision: very often - visual impairment, increased lacrimation.
    From the cardiovascular system: very often - increased blood pressure; often - chronic heart failure, supraventricular tachycardia, arterial thromboembolism, deep vein thrombosis, bleeding, including pulmonary, intracranial, mucosa and skin, GIT and tumor.
    On the part of the respiratory system: very often - shortness of breath, nosebleeds, rhinitis; often - thromboembolism of the pulmonary artery (PE), hypoxia.
    From the gastrointestinal tract: very often - anorexia, diarrhea, nausea, vomiting, constipation, stomatitis, rectal bleeding; often - perforation of the gastrointestinal tract, intestinal obstruction, including obturation, abdominal pain, gastrointestinal disorders.
    On the part of the reproductive system: very often, failure of ovarian function (amenorrhea lasting 3 months or more (follicle stimulating hormone (FSH) concentration> 30 mIU / ml with a negative pregnancy test with determination of human beta-chorionic gonadotropin (3-HCG) in serum).
    From the skin and subcutaneous fat: very often - exfoliative dermatitis, dry skin, discoloration of the skin; often - palmar-plantar syndrome.
    From the musculoskeletal system: very often - arthralgia; often - wewEternal weakness, myalgia.
    From the urinary system: very often - proteinuria; often - infection of the urinary tract.
    Local reactions: very often - pain, including at the injection site.
    Other: very often - asthenia, increased fatigue, pyrexia, inflammation of the mucous membranes of different locations; often - lethargy, inhibition, sepsis, abscess, attachment of secondary infections, dehydration.
    Violations from laboratory indicators:
    hyperglycemia, hypokalemia, hyponatremia, increased prothrombin time, an increase in the international normalized ratio (INR).
    Postmarketing surveillance.
    From the nervous system: hypertensive encephalopathy (very rarely); syndrome of posterior reversible encephalopathy (rarely).
    From the cardiovascular system: thrombotic microangiopathy of the kidneys, clinically manifested by proteinuria (incidence is unknown).
    On the part of the respiratory system: perforation of the nasal septum (incidence is unknown), pulmonary hypertension (incidence is unknown), dysphonia (chahundred).
    From the gastrointestinal tract: Gastrointestinal ulcer (incidence is unknown).
    From the liver and bile ducts: perforation of the gallbladder (incidence is unknown).
    Allergic and infusion reactions: hypersensitivity reactions, infusion reactions (incidence is unknown); with the following possible simultaneous manifestations: dyspnea / difficulty breathing, "hot flashes" / redness / rash, decreased or increased blood pressure, decreased oxygen saturation, chest pain, chills and nausea / vomiting.
    From the musculoskeletal system: osteonecrosis of the jaw (mainly in patients who received concomitant bisphosphonate therapy or who received bisphosphonate therapy earlier).
    Other: necrotizing fasciitis, as a rule, against the background of a violation of wound healing, perforation of the gastrointestinal tract, or fistula formation (rarely).
    Overdose:

    Whenever bevacizumab is given at a maximum dose of 20 mg / kg every 2 weeks, several patients have a headache (migraine) of severe severity severely intravenously. In case of an overdose, the above-mentioned dose-dependent side effects may increase. There is no specific antidote. Treatment is symptomatic.

    Interaction:
    The effect of antitumor drugs on the pharmacokinetics of Avastin®.
    There was no clinically significant effect on the pharmacokinetics of the Avastin® preparation when combined with chemotherapy. There were no statistically or clinically significant differences in the clearance of Avastin® in patients receiving monotherapy and in patients who received Avastin® in combination with interferon alpha-2a or other chemotherapeutic drugs (IFL, FU / LV, carboplatin / paclitaxel, capecitabine, doxorubicin or cisplatin / gemcitabine).
    Effect of Avastin® on the pharmacokinetics of other antitumor drugs.
    Avastin® does not significantly affect the pharmacokinetics of irinotecan and its active metabolite (SN38); capecitabine and its metabolites, as well as oxaliplatin (determined by the free and total level of platinum); interferon alfa-2a; cisplatin.
    There is no reliable data on the effect of Avastin® on the pharmacokinetics of gemcitabine.
    Combination Avastin® and sunitinib.
    When using Avastin® (10 mg / kg once every 2 weeks) in combination with sunitinib (50 mg daily), cases of development of microangiopathic hemolytic anemia (MAGA) have been reported in patients with metastatic renal cell carcinoma. MAGA belongs to a subgroup of hemolytic anemia, which can be manifested by erythrocyte fragmentation, anemia and thrombocytopenia. Some patients additionally have neurologic disorders, increased creatinine concentrations, hypertension, including hypertensive crisis. These symptoms were reversible after discontinuation of therapy with bevacizumab and sunitinib.
    Radiation therapy.
    When Avastin® is used in combination with radiotherapy and chemotherapy (temozolomide) in patients with newly diagnosed glioblastoma, the safety profile of the drug remains unchanged.
    The safety and efficacy of Avastin® in combination with radiotherapy for other indications is not established.
    Avastin® Pharmaceuticalswe take a swallow with solutions of dextrose.

    Special instructions:
    In the patient's medical records, the trade name of the drug (Avastin®) should be indicated. Replacement of the drug with any other biological medicinal product requires agreement with the attending physician. The information provided in this manual applies only to Avastin®.
    Treatment with Avastin® can be done only under the supervision of a doctor who has experience in the use of antitumor therapy.
    In patients receiving Avastin®, there is an increased risk of developing Perforation of the gastrointestinal tract (GIT) and gallbladder. There were severe cases of perforation of the gastrointestinal tract, including fatal (in 0.2% -1% of all patients receiving Avastin®). The clinical picture of perforations of the gastrointestinal tract differed in severity and varied depending on the signs of free gas in the radiography of the abdominal cavity, which disappeared without treatment, before perforations with abscess of the abdominal cavity and lethal outcome.In some cases, the initial intraperitoneal inflammation occurred as a result of gastric ulcer, tumor necrosis, diverticulitis or colitis associated with chemotherapy. The relationship between the development of intra-abdominal inflammation and GI tract perforations and Avastin® therapy has not been established. With the development of perforation of the gastrointestinal tract, treatment with Avastin® should be discontinued.
    With Avastin® treatment serious cases of fistulas, including fatal cases. Gastrointestinal fistulas often occurred in patients with metastatic colorectal cancer and ovarian cancer (up to 2% of patients), less often with other tumor localizations. Occasionally (> 0.1% - <1%), cases of formation of fistulas of other sites (bronchopleural, urogenital, biliary) were recorded. The formation of fistulas is more often observed in the first 6 months of Avastin® treatment, but may occur in 1 week or 1 year and later after the initiation of therapy.
    If there is a tracheoesophageal fistula or fistula of any location of the 4th degree of severity, treatment with Avastin® should be discontinued.There is limited information about the continued use of Avastin® in patients with fistulae of other sites. If there is an internal fistula that does not penetrate the digestive tract, then the question of cancellation of Avastin® should be considered.
    In patients receiving Avastin®, the risk of bleeding, especially bleeding from the tumor. Avastin® should be withdrawn if bleeding occurs in grade 3 or 4 according to the NCI-CTC classification. The overall incidence of bleeding 3-5 degrees of severity with Avastin® for all indications is 0.4% -6.5%. Most often, bleeding from the tumor or small bleeding from the mucous membrane and skin (for example, epistaxis) was observed. Most often observed nosebleeds 1 severity classification NCI-CTC, which lasted less than 5 minutes, resolved without medical intervention and did not require changes in dosage regimen Avastin *. The frequency of minor bleeding from the mucous membrane and the skin depends on the dose of the drug. Less frequent bleeding gums or vaginal bleeding.Abundant or massive pulmonary hemorrhage / hemoptysis was observed mainly with non-small cell lung cancer. Admission of anti-rheumatic / anti-inflammatory drugs, anticoagulants, previous radiation therapy, atherosclerosis, central tumor location, cavity formation before or during treatment are possible risk factors for pulmonary hemorrhage / hemoptysis, with only statistically significant association with the development of hemorrhages for squamous cell lung cancer only. Patients who have recently had bleeding / hemoptysis (more than 2.5 ml blood) should not receive Avastin®.
    Patients with colorectal cancer may have bleeding related to the tumor, including rectal bleeding and melena.
    Bleeding was rare, including intracranial hemorrhage, in patients with metastatic central nervous system (CNS) lesions or with glioblastoma.
    It is necessary to monitor the symptoms of intracranial hemorrhage, if they occur, cancel Avastin®.
    Patients with congenital hemorrhagic diathesis, acquired by coagulopathy or who received a full dose of anticoagulants for thromboembolism, caution should be exercised before Avastin® is given because of a lack of information on the safety profile of the drug among such patients. There was no increase in the incidence of bleeding of grade 3 and higher in patients receiving Avastin® and warfarin.
    Individual cases have been reported, as well as a series of cases of serious adverse events from the side of the organ of vision (including infectious endophthalmitis and other inflammatory diseases) after unregistered intravitreal administration of Avastin®. Some of these phenomena led to loss of visual acuity of varying severity, including persistent blindness. Avastin® is not intended for intravitreal administration.
    Patients receiving Avastin® received an increased incidence arterial hypertension of all degrees of severity (up to 42.1%). For all indications, the frequency of arterial hypertension 3-4 degrees of severity according to the NCI-CTC classification was 0.4% -17.9%; 4 degrees of severity (hypertensive crisis) was observed in 1% of patients.
    Clinical safety data suggest that the incidence of elevated blood pressure (BP) is probably dependent on the dose of bevacizumab. The drug Avastin® can be prescribed only to patients with pre-compensated hypertension with further control of blood pressure. Information on the effect of Avastin® in patients with uncontrolled hypertension at the time of initiation of therapy is not available. In patients with hypertension requiring drug therapy, it is recommended to temporarily discontinue Avastin® therapy until normalization of blood pressure is achieved.
    In most cases, the normalization of blood pressure is achieved with the help of standard antihypertensive agents (angiotensin converting enzyme (ACE) inhibitors, diuretics and blockers of "slow" calcium channels), selected individually for each patient. The withdrawal of Avastin® therapy or hospitalization was rarely required.
    Very few cases were observed hypertensive encephalopathy, some with a fatal outcome. The risk of arterial hypertension associated with Avastin®,does not correlate with the initial characteristics of the patient, concomitant disease or concomitant therapy.
    Therapy with Avastin® should be discontinued in the absence of normalization of AD, the development of hypertensive crisis or hypertensive encephalopathy.
    With Avastin®, single cases have been reported syndrome of posterior reversible encephalopathy, manifested epileptic seizure, headache, mental disorders, visual impairment, damage to the visual centers of the cerebral cortex, with or without hypertension and other symptoms. The diagnosis can be confirmed using brain imaging techniques (preferably using magnetic resonance imaging (MRI)). In case of development of a syndrome of a back reversible encephalopathy it is necessary to appoint or nominate symptomatic therapy, carefully supervise a BP and to cancel preparation Avastin®. Usually resolution or improvement of symptoms occurs in a few days, but neurological complications were observed in some patients. The safety of re-administration of Avastin® in such patients has not been established.
    With Avastin® in combination with chemotherapy, the frequency arterial thromboembolism, including stroke, transient ischemic attack and myocardial infarction and other phenomena of arterial thromboembolism was higher than with the appointment of chemotherapy alone. The overall incidence of arterial thromboembolism was 5%. If arterial thromboembolism occurs, Avastin® should be discontinued. Arterial thromboembolism in history, diabetes mellitus, or age 65 or older is associated with an increased risk of arterial thromboembolism during treatment with Avastin. Care should be taken when treating such patients.
    During treatment with Avastin®, there is an increased risk of developing venous thromboembolism (PE, deep vein thrombosis, thrombophlebitis). The overall incidence of venous thromboembolism (deep vein thrombosis and PE) varies from 2.8% to 17.3%.
    Therapy with Avastin® should be discontinued if there is a life-threatening phenomenon (4 severity) of venous thromboembolism, including PE, and with severity of venous thromboembolism ≤3, careful monitoring of the patient's condition should be carried out.
    Chronic heart failure (CHF) occurred when Avastin® was used for all indications, but mainly for metastatic breast cancer. There was an asymptomatic decrease in the left ventricular ejection fraction and CHF that required therapy or hospitalization.
    CHF of 3 severity and higher was observed in 3.5% of patients treated with Avastin®. In patients treated with Avastin® in combination with anthracycline-based drugs, the incidence of CHF of 3 severity and higher did not differ from the available data in the treatment of metastatic breast cancer. In most patients, there was an improvement in the symptoms and / or fraction of the left ventricular ejection with appropriate treatment.
    Data on the risk of CHF in patients with CHF II-IV class according to the classification of the New York Heart Association (NYHA) are not available in history.
    In most cases, CHF occurred in patients with metastatic breast cancer who received therapy with anthracyclines, radiation therapy on the chest area in the anamnesis or with other risk factors for the development of CHF.
    Caution should be exercised in prescribing Avastin® to patients with a history of clinically significant cardiovascular disease, such as ischemic heart disease or CHF.
    In patients who did not receive therapy with anthracycline-based drugs earlier, with Avastin® and anthracycline-based drugs, there was no increase in the incidence of CHF of any severity compared with monotherapy with anthracycline-based drugs. CHF 3 severity and higher occurred somewhat more frequently in the Avastin® treatment group in combination with chemotherapy compared with chemotherapy alone, which is consistent with other data obtained in patients with metastatic breast cancer who are not receiving concomitant anthracycline therapy.
    In patients with diffuse large B-cell lymphoma with the treatment of bevacizumab and doxorubicin in a cumulative dose of more than 300 mg / m 2, there was an increase in the number of new cases of CHF. When comparing rituximab / cyclophosphamide / doxorubicin / vincristine / prednisolone therapy (R-CHOP) + bevacizumab and R-CHOP, the number of new cases did not differ, but was higher,than observed earlier in therapy with doxorubicin. The incidence of CHF was higher in the R-CHOP + bevacizumab.
    Avastin® can adversely affect on the healing of wounds. Bevacizumab should be treated at least 28 days after extensive surgery or with a complete healing of the surgical wound. When developing complications related to wound healing during treatment, Avastin® should be temporarily discontinued until the wound is completely healed. The administration of Avastin® should also be temporarily discontinued in the event of a planned surgical intervention.
    Rare cases are registered necrotizing fasciitis (including fatal) in patients treated with Avastin®. This phenomenon, as a rule, developed against the background of a violation of wound healing, perforation of the gastrointestinal tract or the formation of fistulas.
    In the case of necrotizing fasciitis, Avastin® should be withdrawn and promptly started treatment.
    Proteinuria 0.7% -38% of patients receiving Avastin® were observed.In terms of severity, proteinuria varied from transient asymptomatic traces of protein in the urine and in 1.4% of patients to nephrotic syndrome (proteinuria of the 4th degree of severity). Proteinuria of the third degree of severity was registered in 8.1% of patients who received the Avastin ® preparation for different indications. Proteinuria was not associated with impaired renal function and rarely required the abolition of Avastin®.
    The risk of developing proteinuria is increased in patients with an arterial hypertension in the anamnesis. Probably, proteinuria of the 1st degree depends on the Avastin® dose.
    With the development of proteinuria of the 4th degree Avastin® preparation must be canceled. It is recommended that an urine test for proteinuria is recommended before and during Avastin® therapy.
    In most cases with proteinuria> 2 g / day, Avastin 8 treatment was temporarily suspended until proteinuria decreased <2 g per day.
    When Avastin® was administered in combination with myelotoxic regimens of chemotherapy, there was an increase in the incidence of development severe neutropenia, febrile neutropenia or infections with severe neutropenia (including fatal cases).
    Patients may have an increased risk of developing infusion reactions / reactions hypersensitivity. There is evidence of a more frequent development of anaphylactic reactions and anaphylactoid type reactions in patients who received Avastin® in combination with chemotherapy compared to patients receiving chemotherapy alone. It is recommended that the patient be closely monitored during and after Avastin®. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical measures taken. Systematic premedication can not be a guarantee of the absence of infusion reactions / hypersensitivity reactions.
    Osteonecrosis of the jaw. There were reports of cases of osteonecrosis of the jaw in cancer patients receiving Avastin®. Most of these patients received bisphosphonates intravenously or as concomitant therapy; osteonecrosis of the jaw is an identified risk for bisphosphonates.
    Care should be taken when using Avastin® and bisphosphonates intravenously at the same time or sequentially.
    Invasive dental procedures are also an identified risk factor. Before starting treatment with Avastin®, a dental examination and appropriate preventive dental procedures should be performed. If possible, avoid invasive dental procedures in patients who have previously received or are currently receiving bisphosphonates intravenously.
    Patients over 65 years of age: with the appointment of Avastin® to patients older than 65 years, there is an increased risk of arterial thromboembolism (including stroke, transient ischemic attack, myocardial infarction), leukopenia 3-4 degrees of severity and thrombocytopenia, as well as neutropenia (all degrees of severity), diarrhea, nausea, headache and fatigue compared with patients <65 years of age. An increase in the incidence of other adverse reactions associated with Avastin® (gastrointestinal perforation, complications associated with wound healing, hypertension, proteinuria, CHF and bleeding) in patients older than 65 years compared with patients <65 years was not noted.
    Men and women of childbearing age During treatment with Avastin® and, at least 6 months after the end of treatment, reliable methods of contraception should be used.
    Avastin® can impair fertility among women. In most patients, fertility was restored after Avastin® was discontinued. The long-term effects of Avastin® therapy on fertility are unknown. Breastfeeding is not recommended during treatment with Avastin® and for at least 6 months after the Avastin® treatment is over.
    Disposal of an unused product or expired must be performed in accordance with the requirements of the medical institution.
    Effect on the ability to drive transp. cf. and fur:

    Studies to study the effect of the drug on the ability to drive vehicles and mechanisms were not carried out. Patients who experience such undesirable effects as syncope, drowsiness, or visual impairment should refrain from managing vehicles and mechanisms.

    Form release / dosage:

    Concentrate for the preparation of a solution for infusions of 100 mg / 4 ml and 400 mg / 16 ml.

    Packaging:100 mg / 4 ml or 400 mg / 16 ml of the product in a glass bottle (glass of hydrolytic class I EF) of butyl rubber stoppers laminated fluoropolymer crimped aluminum cap and closed by a plastic cover. 1 bottle together with the instruction for use is placed in a cardboard box.
    Packing at "ORTAT" CJSC:
    1 vial is placed into a plastic or cardboard tray which, together with instructions for use placed in a pile of cardboard packagings for consumer subgroups chrome-ersatz GOST 7933-89 or imported. For the purpose of controlling the first opening, stickers with the logo of JSC "ORTAT" are glued on the pack.
    Storage conditions:

    Store at 2-8 ° C in a dark place.

    Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-000533
    Date of registration:17.03.2009/20.09.2016
    Expiration Date:Unlimited
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp21.01.2017
    Illustrated instructions
      Instructions
      Up