Avegra® BIOCAD (Avegra BIOCAD)

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

    1 ml of the solution contains:

    Active substances: Bevacizumab 25 mg.

    Excipients: α, trehalose dihydrate 60 mg, sodium dihydrogen phosphate monohydrate 5.8 mg, sodium hydrogen phosphate 1.2 mg, polysorbate 20 0.4 mg, water for injection up to 1.0 ml.

    Description:

    Transparent or opalescent liquid from colorless to light brown in color.

    Pharmacotherapeutic group:Antineoplastic agent, monoclonal antibodies
    ATX: & nbsp

    L.01.X   Other antineoplastic agents

    Pharmacodynamics:

    Preparation Avegra® BIOCAD (bevacizumab) a hyperchimeric monoclonal antibody,

    - a humanized recombinant which selectively binds to a biologically active vascular endothelial growth factor (vascular endothelial growth factor - VEGF) and neutralizes it. Bevacizumab 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 decrease 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 is produced 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 bevacizumab has not been studied.

    When animals were administered bevacizumab, embryotoxic and teratogenic effects were observed.

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

    Pharmacokinetics:

    The pharmacokinetics of bevacizumab following intravenous administration (iv) at various doses (0.1-10 mg / kg every 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. The distribution of bevacizumab is characterized by low clearance, low volume distribution in the central chamber (Vc) and a long half-life, which allows to maintain the required therapeutic concentration of the drug in the plasma with the administration once every 2-3 weeks.

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

    According to population pharmacokinetic meta-analysis, there was no significant difference in the pharmacokinetics of bevacizumab versus race when included in body weight analysis or age-dependent (correlation between clearance creatinine and the patient's age is absent [median age is 59 years, and 5th and 95th percentiles are 37 and 76 years]).

    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-bevacizumab 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 IgG, those. 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 volume 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 the first line of therapy in addition to chemotherapy on the basis of platinum preparations;

    - as the first line of therapy for common inoperable, metastatic or recurring non-squamous non-small cell lung cancer with activating mutations in the EGFR gene (epidermal growth factor receptor) in combination with erlotinib.

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

    Persistent, recurrent or metastatic cervical cancer:

    - in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

    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 therapy with bevacizumab; 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.

    Pregnancy and lactation:

    The use of the drug is contraindicated in pregnancy.

    Women of childbearing age during treatment with Avegra® BIOKAD and, at least 6 months after the end of treatment, should use reliable methods of contraception.

    Breastfeeding is not recommended during treatment with Avegra® BIOKAD and for at least 6 months after the end of Avegra® BIOCAD therapy.

    Dosing and Administration:

    Preparation Avegra® BIOCAD is administered only intravenously by drip; You can not inject the drug intravenously!

    The drug Avegra® BIOCAD is not intended for intravitreal administration.

    The drug Avegra® BIOCAD is pharmaceutically incompatible with dextrose solutions. The necessary amount of Avegra® BIOCAD preparation is diluted to the required volume with 0.9% sodium chloride solution in compliance 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 within 90 minutes as an 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 Avegra® BIOCAD because of undesirable effects. If necessary, treatment with Avegra® BIOKAD should be stopped completely or temporarily.

    Standard dosing regimen

    Metastatic colorectal cancer:

    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 to use Avegra® BIOCAD therapy before signs of disease progression or to unacceptable toxicity.

    As a second line of therapy: patients previously treated with Avegra® BIOCAD can, after the first progression of the disease, continue treatment with Avegra® BIOCAD under conditions of a change in the chemotherapy regimen:

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

    Locally recurrent or metastatic breast cancer (BC):

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

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD should be discontinued.

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

    - The first line of non-small-cell lung cancer therapy in combination with platinum-based chemotherapy

    Preparation Avegra® BIOCAD is prescribed in addition to chemotherapy on the basis of platinum preparations (maximum duration of chemotherapy is 6 cycles), then the introduction of the drug Avegra® BIOCAD continues as a monotherapy. If there is evidence of progression of the disease or unacceptable toxicity, Avegra® The biocad 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.

    - The first line of non-small-cell lung cancer therapy with activating mutations in the gene EGFR in combination with erlotinib

    15 mg / kg once every 3 weeks as an intravenous infusion in addition to erlotinib therapy.

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD should be discontinued.

    For information on patient selection and doses, see the complete medical instructions for erlotinib.

    Common and / or metastatic renal cell carcinoma:

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

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD should be discontinued.

    Glioblastoma (grade IV glioma according to WHO classification):

    With a newly diagnosed disease: 10 mg / kg once every 2 weeks in the form of intravenous infusion in combination with radiotherapy and temozolomide, during 6 weeks. After a 4-week break, the administration of Avegra® BIOCAD 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, the administration of the drug Avegra® BIOCAD continues as monotherapy at a dose of 15 mg / kg once every 3 weeks.

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD 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, therapy with Avegra® BIOKAD should be discontinued.

    Epithelial cancer of the ovary, uterine 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 the introduction of the drug Avegra® BIOCAD continues as a monotherapy. The total duration of therapy with Avegra® BIOKAD is 15 months.

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD 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 the introduction of the drug Avegra® BIOCAD continues as a monotherapy.

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD 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 therapy with Avegra® BIOKAD should be discontinued.

    Persistent, recurrent or metastatic cervical cancer

    15 mg / kg once every 3 weeks as an intravenous infusion in combination with chemotherapeutic regimens: paclitaxel and cisplatin or paclitaxel and topotecan.

    If signs of disease progression or unacceptable toxicity appear, therapy with Avegra® BIOKAD should be discontinued.

    Use in special patient groups

    Children and teens

    The safety and efficacy of Avegra® BIOCAD in children and adolescents have not been established. A drug Bevacizumab is contraindicated in children under 18 years of age. The publications described the observed in the recipients bevacizumab patients under the age of 18 years of cases of osteonecrosis of various locations other than osteonecrosis of the jaw.

    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, treatment and destruction

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

    The drug Avegra® BIOCAD does not contain an antimicrobial preservative, so it is necessary to ensure 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 who received bevacizumab, 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.

    Below are the adverse reactions of all severity levels according to the classification of the National Cancer Institute (NCI-CTC), observed in patients who received bevacizumab 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%), the frequency is unknown.

    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, however bevacizumab in combination with chemotherapeutic drugs can enhance the manifestations of these reactions. Examples include palmar-plantar syndrome with capecitabine or pegylated liposomal doxorubicin, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail damage, or alopecia with paclitaxel therapy.

    Violations from the blood and lymphatic system: very often - febrile neutropenia, leukopenia, neutropenia, thrombocytopenia; often - anemia, lymphocytopenia.

    Impaired nervous system: very often - peripheral sensory neuropathy, dysgeusia, headache, dysarthria; often - stroke, syncope, drowsiness.

    Disorders from the side of the organ of vision: very often - visual impairment, increased lacrimation.

    Heart Disease: often - chronic heart failure, supraventricular tachycardia.

    Vascular disorders: very often - increased blood pressure, venous embolism; often - arterial thromboembolism, deep vein thrombosis, bleeding, including pulmonary, intracranial, from the mucosa and skin, GIT and from the tumor.

    Disturbances from the respiratory system, chest and mediastinal organs: very often - shortness of breath, nosebleeds, rhinitis; often - pulmonary hemorrhage, hemoptysis, pulmonary embolism (PE), hypoxia.

    Disorders from the gastrointestinal tract: very often - anorexia, diarrhea, nausea, vomiting, abdominal pain, constipation, stomatitis, rectal bleeding; often - perforation of the gastrointestinal tract, intestinal obstruction, including obturation, fistulas between the vagina and rectum (the most common variant of fistulas between the vagina and the gastrointestinal tract), gastrointestinal disorders, pain in the rectum.

    Disorders from the liver and bile ducts: frequency unknown - perforation of the gallbladder.

    Disturbances from the skin and subcutaneous tissues: very often - complications of wound healing, exfoliative dermatitis, dry skin, discoloration of the skin; often - palmar-plantar syndrome, inflammation of subcutaneous fat.

    Disturbances from the musculoskeletal and connective tissue: very often - arthralgia; often - fistula, muscle weakness, myalgia, back pain.

    Disorders from the kidneys and urinary tract: very often - proteinuria; often - infection of the urinary tract.

    Violations of the genitals and breast: very often - failure of ovarian function (amenorrhea lasting 3 months or more (follicle stimulating hormone (FSH) concentration> 30 mIU / ml with negative pregnancy test with the definition of beta-chorionic gonadotropin in human β-hCG) in the serum), often - pain in the small pelvis.

    General disorders and disorders at the site of administration: very often - pain, including at the injection site, asthenia, increased fatigue, pyrexia, inflammation of the mucous membranes of various locations, weight loss, paronychia; often - lethargy, inhibition, sepsis, abscess, cellulitis, attachment of secondary infections, dehydration.

    Laboratory and instrumental data: hyperglycemia, hypokalemia, hyponatremia, an increase in prothrombin time, an increase in the international normalized relationship (INR).

    Post-registration experience with bevacizumab

    Impaired nervous system: rarely - reverse reversible encephalopathy syndrome; very rarely - hypertensive encephalopathy.

    Vascular disorders: frequency unknown - thrombotic microangiopathy of the kidneys clinically manifested by proteinuria.

    Disturbances from the respiratory system, chest and mediastinal organs: often - dysphonia; frequency unknown - perforation of nasal septum, pulmonary hypertension.

    Disorders from the gastrointestinal tract: frequency unknown - gastrointestinal ulcer.

    Disorders from the liver and bile ducts: frequency unknown - perforation of the gallbladder.

    Disturbances from the musculoskeletal and connective tissue: frequency unknown - osteonecrosis of the jaw (mainly in patients who received concomitant bisphosphonate therapy or who received bisphosphonate therapy earlier), osteonecrosis of other localization (not mandibular).

    General disorders and disorders at the site of administration: rarely - necrotizing fasciitis, as a rule, against a background of wound healing, perforation of the gastrointestinal tract, or fistula formation; frequency is unknown - hypersensitivity reactions, infusion reactions, 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.

    Congenital, hereditary and genetic disorders: cases of abnormalities of fetal development were observed in women who received bevacizumab in monotherapy or in combination with known embryotoxic chemotherapeutic drugs.

    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:

    Pharmacokinetic interaction

    The effect of antitumor drugs on the pharmacokinetics of bevacizumab:

    There was no clinically significant effect on the pharmacokinetics of bevacizumab when combined with chemotherapy. There were no statistically or clinically significant differences in the clearance of bevacizumab in patients receiving monotherapy and in patients who received bevacizumab in combination with interferon alpha-2a, erlotinib or chemotherapeutic drugs (IFL, FU / LV, carboplatin / paclitaxel, capecitabine, doxorubicin or cisplatin / gemcitabine).

    The influence of bevacizumab on the pharmacokinetics of other antitumor drugs:

    There was no clinically significant effect of bevacizumab on the pharmacokinetics of concomitant drugs: interferon alfa-2a, erlotinib (and its active metabolite OSI-240); or chemotherapeutic drugs: irinotecan (and its active metabolite SN38), capecitabine, oxaliplatinum, (determined by the free and total level of platinum) and cisplatin.

    There is no reliable data on the effect of bevacizumab on the pharmacokinetics of gemcitabine.

    Pharmacodynamic interaction:

    Combination of bevacizumab and sunitinib:

    In cases of bevacizumab (10 mg / kg once every 2 weeks) in combination with sunitinib (50 mg daily), patients with metastatic renal cell carcinoma have reported cases of development of microangiopathic hemolytic anemia (MAGA). 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.

    Combination with chemotherapy based on platinum or taxane preparations An increase in the incidence of severe neutropenia, febrile neutropenia, or infections with or without severe neutropenia (including fatal cases) was observed mainly in patients who received chemotherapy on the basis of taxanes or platinum drugs for the treatment of non-small cell lung cancer and metastatic breast cancer.

    Radiation therapy:

    When using bevacizumab in combination with radiotherapy and chemotherapy (temozolomide) inpatients with newly diagnosed glioblastoma of new adverse events associated with bevacizumab were not recorded.

    The safety and efficacy of bevacizumab in combination with radiotherapy for other indications is not established.

    Monoclonal antibodies specific for epithelial growth factor receptors (EGFR) human, in combination with chemotherapeutic regimens containing bevacizumab

    Special studies of drug interactions were not conducted. Do not use monoclonal antibodies to epithelial growth factor receptors (EGFR) for the treatment of metastatic colorectal cancer in combination with chemotherapeutic regimens containing bevacizumab. The results of randomized phase III trials (RASSE and CAIRO-23) in patients with metastatic colorectal cancer, it is suggested that the use of monoclonal antibodies to EGFR (panitumumab and cetuximab) in combination with bevacizumab and chemotherapy is associated with a decrease in progression-free survival and / or overall survival and an increase in toxicity when compared to bevacizumab alone and chemotherapy.

    Pharmaceutical interaction

    The drug Avegra® BIOCAD is not pharmaceutically compatible with dextrose solutions.
    Special instructions:

    Treatment with Avegra® BIOCAD can be done only under the supervision of a doctor who has experience in the use of antitumor therapy.

    Perforation of the gastrointestinal tract (GIT) and gallbladder

    In patients receiving bevacizumab, there is an increased risk of 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 who received bevacizumab).

    When using bevacizumab in patients with persistent, relapsing or metastatic cervical cancer, cases of perforation of the gastrointestinal tract (of all severity) were observed in 3.2% of patients, all of whom had previously received radiation therapy. The clinical picture of perforations of the gastrointestinal tract differed in severity and varied from signs of free gas in the radiography of the abdominal cavity, which disappeared without treatment, to 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 intraperitoneal inflammation and perforation of the gastrointestinal tract and therapy with bevacizumab is not established. With the development of perforation of the digestive tract, treatment with Avegra® BIOKAD should be discontinued.

    Whole GI tract

    In patients with metastatic colorectal cancer and ovarian cancer, fistulas of the gastrointestinal tract (of all degrees of severity) occurred in 2% of patients, less often with other tumor localizations. Patients treated with bevacizumab for the treatment of persistent, recurrent or metastatic cervical cancer may have an increased risk of fistula formation between the vagina and any part of the digestive tract (gastrointestinal vaginal fistula).

    When studying the use of bevacizumab in patients with persistent, relapsing or metastatic cervical cancer, the incidence of gastrointestinal vaginal fistula formation was 8.3%, in all cases pelvic radiation was previously performed. Patients with a gastrointestinal vaginal fistula may also have intestinal obstruction and may require surgical intervention, including stoma implantation.

    Fistulas of other localizations (except for the digestive tract)

    Patients may have an increased risk of developing fistulas during therapy with Avegra® BIOKAD. In the treatment with bevacizumab serious cases of fistula formation have been recorded, including fatal cases.

    In the study of bevacizumab in patients with persistent, recurrent or metastatic cervical cancer, the incidence of fistula formation in the unintentionally localized (vaginal, genitourinary or female reproductive tract) was observed in 1.8% of patients who received bevacizumab.

    Infrequently (≥0,1% - <1%) cases of formation of fistulas of other localizations (bronchopleural, biliary) were recorded. The formation of fistulas is more often observed in the first 6 months of therapy with bevacizumab, but may occur as after 1 week, and after 1 year and later after the initiation of therapy.

    If there is a tracheo-esophageal fistula or fistula of any location of 4 degrees of severity, therapy with Avegra® BIOCAD should be discontinued. There is limited information about the continued use of bevacizumab in patients with fistulae of other locations. If an internal fistula does not penetrate the digestive tract, the question of cancellation of the drug Avegra® BIOCAD should be considered.

    Bleeding

    Patients receiving the drug Avegra® BIOCAD increased the risk of bleeding, especially bleeding from the tumor. The drug Avegra® BIOKAD should be discontinued if bleeding occurs at grade 3 or 4 according to classification NCI-CTC. The overall incidence of bleeding 3-5 degrees of severity with bevacizumab for all indications is 0.4% -6.9%. Most often, bleeding from the tumor or small bleeding from the mucous membrane and skin (for example, epistaxis) was observed.

    Most often observed nasal bleeding of 1 degree of severity according to the classification NCI-CTC, lasting less than 5 minutes, resolved without medical intervention and did not require a change in the dosage regimen of bevacizumab. 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. Receiving anti-rheumatic / anti-inflammatory drugs, anticoagulants, previous radiation therapy, atherosclerosis, central location of the tumor,the formation of a cavity before or during treatment are possible risk factors for pulmonary hemorrhage / hemoptysis, and only for squamous cell carcinoma of the lung proved statistically significant association with the development of bleeding.

    Patients who had recent bleeding / hemoptysis (more than 2.5 ml of blood) should not receive the drug Avegra® BIOCAD.

    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 hemorrhages, if they occur, cancel the therapy with Avegra® BIOCAD.

    In patients with congenital bleeding diathesis, acquired coagulopathy or receiving full dose of anticoagulants on the thromboembolism before prescribing the drug Avegra® BIOCAD care should be taken due to lack of information on the safety profile of the drug in these patients.There was no increase in the incidence of bleeding of grade 3 and higher in patients who received bevacizumab and warfarin.

    Disturbances on the part of the organ of sight

    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 infective endophthalmitis and other inflammatory diseases) after unregistered intravitreal administration of bevacizumab. Some of these phenomena led to loss of visual acuity of varying severity, including persistent blindness. The drug Avegra® BIOCAD is not intended for intravitreal administration.

    Arterial hypertension

    When studying the use of bevacizumab, except for patients who received bevacizumab in combination with erlotinib as the first line of non-small cell non-small cell lung cancer therapy with activating mutations in the gene EGFR, the overall incidence of arterial hypertension of all degrees of severity varied (up to 42.1%). The overall incidence of arterial hypertension is 3-4 degrees of severity by classification NCI-CTC was 0.4-17.9%; 4 degrees of severity (hypertensive crisis) was observed in 1% of patients.

    In patients who received bevacizumab, in combination with erlotinib as the first line of non-small cell non-small cell lung cancer therapy with activating mutations in the gene EGFR, Arterial hypertension of all degrees of severity was observed with a frequency of 77.3%; arterial hypertension of the third degree of severity was observed in 60.0% of patients; there were no phenomena of arterial hypertension of the 4th or 5th degree of severity.

    Clinical safety data suggest that the incidence of elevated blood pressure (BP) is probably dependent on the dose of bevacizumab. The drug Avegra® BIOCAD can be prescribed only to patients with pre-compensated arterial hypertension with further control of blood pressure. Information on the effect of bevacizumab in patients with uncontrolled hypertension at the time of initiation of therapy is absent. In patients with hypertension requiring drug therapy, it is recommended that the therapy with Avegra® BIOCAD be temporarily discontinued 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 bevacizumab therapy or hospitalization was rarely required.

    Very rarely there were cases of hypertensive encephalopathy, some with a fatal outcome. The risk of arterial hypertension associated with bevacizumab therapy does not correlate with the patient's baseline characteristics, concomitant disease or concomitant therapy.

    Therapy with the drug Avegra® BIOCAD should be discontinued in the absence of normalization of AD, the development of hypertensive crisis or hypertensive encephalopathy.

    Syndrome of posterior reversible encephalopathy

    In the treatment with bevacizumab, single cases of reverse reversible encephalopathy syndrome, manifested by epileptic seizure, headache, mental disorders, visual impairment, damage to the visual centers of the cerebral cortex, with or without arterial hypertension and other symptoms have been reported. The diagnosis can be confirmed using brain imaging techniques (preferably using magnetic resonance imaging (MRI)). In the case of the development of the syndrome of reversible reversible encephalopathy, symptomatic therapy should be prescribed, the blood pressure should be closely monitored and Avegra® BIOCAD should be withdrawn.Usually resolution or improvement of symptoms occurs in a few days, but neurological complications were observed in some patients. The safety of re-appointment of the drug Avegra® BIOKAD in such patients is not established.

    Arterial thromboembolism

    In therapy with bevacizumab in combination with chemotherapy, the frequency of 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 5.9% (0.8% fatal). When arterial thromboembolism occurs, therapy with Avegra® BIOCAD should be discontinued. Arterial thromboembolism in history, diabetes mellitus or age over 65 years are associated with an increased risk of arterial thromboembolism during treatment with bevacizumab. Care should be taken when treating such patients.

    Venous thromboembolism

    During treatment with Avegra® BIOKAD, there is an increased risk of 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%.

    The phenomena of venous thromboembolism of 3-5 degrees of severity were reported in 7.8% of patients who received bevacizumab in combination with chemotherapy. In patients who have experienced the phenomenon of venous thromboembolism and who are receiving bevacizumab therapy and chemotherapy, there is an increased risk of recurrence of venous thromboembolism.

    Patients who received bevacizumab for treatment of persistent, recurrent or metastatic cervical cancer, have an increased risk of venous thromboembolism. Phenomena of 3-5 degrees of severity were observed in 10.6% of such patients.

    The phenomena of venous thromboembolism of 3-5 degrees of severity were reported in 7.6% of patients with newly diagnosed glioblastoma who received bevacizumab in combination with chemotherapy and radiotherapy, compared with 8.0% of patients receiving chemotherapy and radiation therapy.

    The therapy with Avegra® BIOKAD should be discontinued if there is a life-threatening phenomenon (4 severity) of venous thromboembolism, including PE, and if the degree of severity of venous thromboembolism <3 should be carefully monitored for the patient.

    Chronic heart failure

    Chronic heart failure (CHF) occurred with bevacizumab in all indications, but mainly with 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 who received bevacizumab. In patients who received bevacizumab 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) in the anamnesis are absent.

    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 when prescribing Avegra® BIOCAD 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 agents earlier, with bevacizumab and anthracycline-based drugs, there was no increase in the incidence of CHF of any severity compared with monotherapy drugs anthracycline. CHF 3 degrees of severity and higher there were several more often in the group of therapy with bevacizumab in combination with chemotherapy compared with chemotherapy alone, which is consistent with other data obtained in patients with metastatic breast cancer and 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, there was an increase in the number of new cases of CHF. When comparing rituximab / cyclophosphamide / doxorubicin / vincristine / prednisone therapy (R-CHOP) + bevacizumab and R-CHOP the number of new cases did not differ, but was higher than that observed earlier with doxorubicin therapy. The incidence of CHF was higher in the group R-CHOP + bevacizumab.

    Healing of wounds

    Avegra® BIOCAD can adversely affect the healing of wounds.With the use of bevacizumab, severe complications of wound healing with lethal outcome were recorded. Treatment with Avegra® BIOKAD should be started no less than 28 days after extensive surgery or with full healing of a surgical wound. When developing complications related to wound healing during treatment, Avegra® BIOCAD should be temporarily discontinued until the wound is completely healed. The introduction of the drug Avegra® BIOCAD should also be temporarily discontinued in the event of a planned surgical intervention.

    In the treatment of newly diagnosed glioblastoma, the frequency of postoperative complications of wound healing of 3-5 degrees of severity (including complications after craniotomy) was 3.3% in patients who received bevacizumab in combination with chemotherapy and radiotherapy.

    Necrotizing fasciitis

    Rare cases of necrotizing fasciitis (including fatal cases) were registered in patients treated with bevacizumab. 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, Avegra® BIOKAD should be withdrawn and promptly started treatment.

    Proteinuria

    Proteinuria was observed in 0.7% -54.7% of patients who received bevacizumab. 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 grade 4 gravity). Proteinuria of 3 severity was recorded in 8.1% of patients who received bevacizumab for various indications.

    The risk of developing proteinuria is increased in patients with an arterial hypertension in the anamnesis. Probably, proteinuria 1 degree depends on the dose of bevacizumab.

    With the development of nephrotic syndrome, the preparation of Avegra® BIOCAD must be discontinued.

    Before and during the treatment with Avegra® BIOKAD it is recommended to perform a urine test for proteinuria. In most cases with proteinuria> 2 g per day, therapy with bevacizumab was temporarily suspended until proteinuria decreased <2 g per day.

    Hematologic disorders

    When therapy with bevacizumab in combination with myelotoxic regimens of chemotherapy, there was an increase in the frequency of developmentsevere neutropenia, febrile neutropenia, or infections with severe neutropenia (including fatal cases).

    Infusion reactions and hypersensitivity reactions

    Patients may have an increased risk of developing infusion reactions / hypersensitivity reactions. There is evidence of a more frequent development of anaphylactic reactions and anaphylactoid type reactions in patients who received bevacizumab in combination with chemotherapy, compared with patients who received only chemotherapy. In the study of bevacizumab, such reactions were often observed (in 5% of patients who received bevacizumab).

    It is recommended to carefully monitor the patient during and after the administration of the drug Avegra® BIOCAD. 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

    Cases of osteonecrosis of the jaw were reported in cancer patients who received bevacizumab. Most of these patients received bisphosphonates intravenously or as concomitant therapy; osteonecrosis of the jaw is an identified risk for bisphosphonates.

    Caution should be exercised when using the drug Avegra® BIOCAD and bisphosphonates intravenously simultaneously or sequentially.

    Invasive dental procedures are also an identified risk factor. Before starting treatment with Avegra® BIOKAD, 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.

    Infections

    When studying bevacizumab in combination with chemotherapy and radiotherapy in patients with newly diagnosed glioblastoma, the incidence of infections of any severity was 54.4% (12.8% for 3-5 grade infections).

    Violations from laboratory indicators

    When studying bevacizumab, a transient increase in serum creatinine concentration (1.5-1.9 times higher than baseline) was noted with the presence or absence of proteinuria.The observed increase in serum creatinine concentration was not associated with a higher incidence of clinical trialsphenomena of impaired renal function in patients treated with bevacizumab. Patients of advanced age (over 65 years)

    In appointing the drug Avegra® BIOCAD patients over 65 years there is an increased risk of arterial thromboembolic events (including the development of stroke, transient ischemic attack, myocardial infarction), Grade 3-4 leukopenia and thrombocytopenia, and neutropenia (all severities), diarrhea, nausea , headache and fatigue compared with patients ≤ 65 years of age. In the study of bevacizumab with metastatic colorectal cancer increasing incidence of other side-reactions associated with the use of bevacizumab (gastrointestinal perforation, complications associated with wound healing, bleeding and CHF), in patients older than 65 years compared with patients ≤ 65 years were observed.

    Influence on childbearing function

    Men and women of childbearing age during treatment with Avegra® BIOKAD and, at least 6 months after the end of treatment, should use reliable methods of contraception.

    Avegra® BIOCAD can impair fertility in women. In most patients, fertility was restored after discontinuation of therapy with bevacizumab. The long-term effects of bevacizumab therapy on fertility are unknown.

    Breastfeeding is not recommended during drug treatment Avegra® BIOCAD and, at least, within 6 months after the end of therapy preparation Avegra® BIOCAD.

    Disposal of the drug

    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 12.5 mg / 0.5 ml, 100 mg / 4 ml and 400 mg / 16 ml.

    Packaging:

    By 0.5, 4 or 16 ml of the preparation at a concentration of 25 mg / ml into bottles of colorless neutral glass I of the hydrolytic class,Corked with rubber stoppers, with a run-off of aluminum caps. Each label is labeled with a self-adhesive label. For 1 vial (0.5 ml each) into a contour mesh package made of PVC film. 1 contour pack with instructions for use in a pack of cardboard.

    For 1 bottle (4 and 16 ml of the drug), along with instructions for use in a pack of cardboard.

    Storage conditions:

    At a temperature of 2 to 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 expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003336
    Date of registration:25.11.2015 / 07.07.2016
    Expiration Date:25.11.2020
    The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp27.02.2017
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