Avastin concentrate for solution for infusion 400mg N1
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Active ingredients
Bevacizumab
Release form
Concentrate
Pharmacological effect
Antitumor drug. Avastin; (bevacizumab) is a humanized recombinant hyperchimeric monoclonal antibody that binds selectively to a biologically active vascular endothelial growth factor (VEGF) and neutralizes it. Drug Avastin; inhibits the binding of vascular endothelial growth factor to its type 1 and type 2 receptors (Flt-1, KDR) on the surface of endothelial cells, resulting in reduced vascularization and inhibition of tumor growth. Bevacizumab contains fully human framework regions with mouse hyper-chimeric antibody determining complementarity bind to VEGF. Bevacizumab is produced by recombinant DNA technology in an expression system represented by Chinese hamster ovary cells. Bevacizumab consists of 214 amino acids and has a molecular weight of about 149,000 daltons. Introduction of bevacizumab leads to the suppression of metastatic disease progression and reduction of microvascular permeability in various human tumors, including colon, breast, pancreas and prostate cancer. Safety data are clinical and the mutagenic potential of Avastin; not studied. When Avastin was administered to animals; embryotoxic and teratogenic effects were observed. In actively growing animals with open growth zones, use of the drug Avastin; associated with cartilage dysplasia.
Pharmacokinetics
The pharmacokinetics of the drug Avastin was studied; after iv administration in 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 different solid tumors. The pharmacokinetics of bevacizumab, as well as other antibodies, are described by a two-chamber model. The distribution of the drug Avastin; characterized by low clearance, low volume distribution in the central chamber (Vc) and a long half-life (T1 / 2), which helps to maintain the required therapeutic plasma concentration of the drug when administered once every 2-3 weeks. Bevacizumab clearance does not depend on the patient's age .Bevacizumab clearance is 30% higher in patients with low albumin and 7% higher in patients with a large tumor mass compared with patients with average albumin and tumor mass. The distribution of Vc is 2.73 L and 3.28 L in women and men, respectively, which corresponds to the volume of distribution of IgG and other monoclonal antibodies. The volume of distribution in the peripheral chamber (Vp) is 1.69 L and 2.35 L for women and men, respectively, when prescribing Bevacizumab with other anticancer drugs. After dose adjustment with regard to body weight in men, Vc is 20% more than in women. Metabolism After a single IV administration of 125 I-bevacizumab, its metabolic characteristics are similar to those of natural IgG molecules, which do not bind to VEGF. The metabolism and elimination of bevacizumab corresponds to the metabolism and elimination of endogenous IgG, i.e. mainly carried out by proteolytic catabolism in all cells of the body, including endothelial cells, and not through the kidneys and liver. The binding of IgG to neonatal receptors on the crystallizing IgG fragment (FcRn receptors) protects it from cellular metabolism and provides long-lasting T1 / 2.VyvedenieFarmacokinetics of bevacizumab in the dose range from 1.5 to 10 mg / kg per week is linear. days in women and 0.220 l / day in men. After dose adjustment with regard to body weight in men, bevacizumab clearance is 17% more than in women. According to the two-chamber T1 / 2 model for women, it is 18 days, for men - 20 days. Pharmacokinetics in special patient groups Patients of advanced age (over 65 years) and teenagers. Available data indicate that there is no difference between Vd and bevacizumab clearance in children, adolescents and adult patients with solid tumors. Patients with renal or hepatic insufficiency The safety and effectiveness of bevacizumab in patients with renal or hepatic insufficiency has not been studied, as the kidneys and liver are not the main organs of metabolism and elimination of bevacizumab.
Indications
Metastatic colorectal cancer: - in combination with chemotherapy based on fluoropyrimidine derivatives. Local recurrent or metastatic breast cancer: - as the first line of therapy in combination with paclitaxel. A common inoperable, metastatic or recurrent non-squamous non-small cell cell block pattern. therapy in addition to platinum-based chemotherapy. Common and / or metastatic renal cell carcinoma: - as a first-line therapy and in combination with interferon alpha-2a. Glioblastoma (grade IV glioma in WHO classification): - in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma; - in monotherapy or in combination with irinotecan in patients with glioblastoma recurrence or progression diseases. Epithelial cancer of the ovary, fallopian tube and primary cancer of the peritoneum: - as the first line of therapy in combination with carboplatin and paclitaxel with common (IIIB, IIIC and IV stages according to the FIGO classification) ep common cancer of the ovary, uterine tube and primary peritoneal cancer; in combination with carboplatin and gemcitabine for recurrent platinum-sensitive epithelial cancer of the ovary, fallopian tube and primary cancer of the peritoneum in patients who have not previously received bevacizumab or other VEGF inhibitors; in combination with paclitaxel, or topotecan, or pegylated liposomal doxorubicin in relapsed, platinum-resistant epithelial cancer of the ovary, fallopian tube, and primary peritoneal cancer in patients who have previously received no more than two chemotherapy regimens.
Contraindications
- hypersensitivity to bevacizumab or any other component of the drug, preparations based on Chinese hamster ovary cells or to other recombinant human or close to human antibodies; - renal and hepatic insufficiency (efficacy and safety have not been established); - pregnancy; - breastfeeding period - children's age up to 18 years (efficacy and safety have not been established). With caution, a drug should be prescribed for a history of arterial thromboembolism; diabetes; aged patientsover 65 years old; with congenital hemorrhagic diathesis and acquired coagulopathy; taking anticoagulants for the treatment of thromboembolism before starting treatment with Avastin ;; a clinically significant cardiovascular disease (CHD or history of chronic heart failure); hypertension; venous thromboembolism; wound healing; bleeding / hemoptysis; a history of gastrointestinal perforation; posterior reversible encephalopathy syndrome; neutropenia; proteinuria.
Use during pregnancy and lactation
The drug is contraindicated for use during pregnancy and lactation. Men and women of childbearing age during treatment with Avastin; and at least 6 months after the end of treatment, you must use reliable methods of contraception. Avastin; may impair fertility in women. In most patients, fertility was restored after cessation of therapy with Avastin ;. The long-term effects of therapy with Avastin; fertility is unknown. Feeding with breast milk is not recommended during treatment with Avastin; and, at least, within 6 months after the termination of therapy by drug Avastin
Side effects
The most serious adverse reactions include gastrointestinal perforation, hemorrhages, including pulmonary hemorrhage / hemoptysis (more common in patients with non-small cell lung cancer), arterial thromboembolism. In patients who received the drug Avastin; most often observed: increased blood pressure, weakness or asthenia, diarrhea and pain in the abdomen. Increased blood pressure and the development of proteinuria probably has a dose-dependent nature. The adverse reactions of all degrees of severity, according to the National Cancer Institute (NCI-CTC) classification, were found below. ENTOV receiving the drug Avastin; in combination with various chemotherapeutic regimens for all indications. The following criteria are used to describe the frequency of adverse reactions: very often (≥10%), often (≥1% - <10%), infrequently (≥0.1% - <1%), rarely (≥0.01% - <0.1%), very rarely (<0.01%). Unwanted reactions are classified in a specific category according to the highest incidence. Within the same frequency category, adverse reactions are presented in order of severity.Some of the adverse reactions listed are often observed with chemotherapy (for example, palmar-plantar syndrome with capecitabine therapy and peripheral sensory neuropathy with paclitaxel or oxaliplatin therapy); However, we can not exclude a worsening of the state during therapy with Avastin ;. When using the drug Avastin; in combination with pegylated liposomal doxorubicin, the risk of the development of the palm-plantar syndrome may be increased. From the hemopoietic 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. On the part of the organ of vision: very often - impaired vision, increased tearing. On the side of the cardiovascular system: very often - an increase in blood pressure; often - chronic heart failure, supraventricular tachycardia, arterial thromboembolism, deep vein thrombosis, bleeding (including pulmonary, intracranial, mucous membrane and skin, gastrointestinal tract and tumor). On the respiratory system: very often - shortness of breath, nasal bleeding, rhinitis; often - pulmonary embolism (PE), hypoxia. On the part of the digestive system: very often - anorexia, diarrhea, nausea, vomiting, constipation, stomatitis, rectal bleeding; often - gastrointestinal perforation, intestinal obstruction (including obstructive), abdominal pain, gastrointestinal disorders. On the reproductive system: very often - lack of ovarian function (amenorrhea lasting 3 months or more (FSH concentration ≥30 mIU / ml with a negative pregnancy test with human serum beta human chorionic gonadotropin)). From the skin and subcutaneous tissues: very often - exfoliative dermatitis, dry skin, discoloration of the skin; often - palmar and plantar syndrome. From the musculoskeletal system: very often - arthralgia; often - muscular weakness, myalgia. From the urinary system: very often - proteinuria; often - urinary tract infection. Local reactions: very often - pain, incl. in the injection site. Other: very often - asthenia, increased fatigue, pyrexia,inflammation of the mucous membranes of various locations; often - lethargy, lethargy, sepsis, abscess, the addition of secondary infections, dehydration. From laboratory parameters: hyperglycemia, hypokalemia, hyponatremia, an increase in prothrombin time, an increase in MHO.Postmarketing observation On the side of the nervous system: rarely - posterior reversible encephalopathy; very rarely - hypertensive encephalopathy. From the cardiovascular system: the incidence is unknown - thrombotic microangiopathy of the kidney, clinically manifested by proteinuria. From the side of the respiratory system: often - dysphonia; the frequency of occurrence is unknown - nasal septum perforation, pulmonary hypertension. On the gastrointestinal tract: the incidence is unknown - gastrointestinal ulcer. On the liver and biliary tract: the incidence is unknown - gallbladder perforation. Allergic and infusion reactions: the incidence is unknown - hypersensitivity reactions, infusion reactions with the following possible simultaneous manifestations: shortness of breath / difficulty breathing, flushing / redness / rash, decrease or increase in blood pressure, decrease 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 previously received bisphosphonate therapy). Others: rarely - necrotizing fasciitis, usually a background of impaired wound healing, gastrointestinal perforation or fistula formation.
Overdose
When bevacizumab was prescribed at a maximum dose of 20 mg / kg every 2 weeks, a few patients had severe headache (migraine). In case of overdose, it is possible to enhance the listed dose-dependent side effects. There is no specific antidote. Symptomatic treatment.
Interaction with other drugs
The effect of anticancer drugs on the pharmacokinetics of the drug Avastin; There was no clinically significant effect on the pharmacokinetics of the drug Avastin; when combined with chemotherapy use. No statistically or clinically significant differences in clearance of the drug Avastin; in patients treated with monotherapy and in patientstreated with 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 anticancer drugs: Avastin; no significant effect on 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. Reliable data on the effect of Avastin; on the pharmacokinetics of gemcitabine none. The combination of the drug Avastin; and sunitinib when using Avastin; (10 mg / kg 1 time per 2 weeks) in combination with sunitinib (50 mg daily) in patients with metastatic renal cell carcinoma, cases of microangiopathic hemolytic anemia (AHA) have been reported. MAGA belongs to the subgroup of hemolytic anemias, which can manifest as erythrocyte fragmentation, anemia and thrombocytopenia. In some patients, neurological disorders, an increase in the concentration of creatinine, and arterial hypertension, including hypertensive crisis, are additionally noted. These symptoms were reversible after cessation of therapy with bevacizumab and sunitinib. Trauma therapy When using Avastin; in combination with radiation therapy 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 radiation therapy for other indications has not been established. Pharmaceutical interaction: Avastin; pharmaceutically incompatible with dextrose solutions.
special instructions
In the medical records of the patient should indicate the trade name of the drug (Avastin;). Replacing the drug with any other biological drug requires coordination with your doctor. The information presented in this description applies only to the drug Avastin;. Treatment with the drug Avastin; can only be carried out under the supervision of a physician with experience in the use of anticancer therapy. Patients receiving the drug Avastin; there is an increased risk of developing gastrointestinal perforation and the gall bladder. There were severe cases of perforation of the gastrointestinal tract, including and fatal (in 0.2-1% of all patients receiving the drug Avastin;).The clinical picture of gastrointestinal perforations differed in severity and varied depending on the signs of free gas in abdominal radiography, which disappeared without treatment, before perforations with abscess of the abdominal cavity and death. In some cases, 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 gastrointestinal perforations and drug therapy Avastin; not installed. With the development of gastrointestinal perforation treatment with Avastin; should be stopped. When treated with Avastin; serious cases of fistula formation, including fatal cases, have been reported. Fistulas of the gastrointestinal tract most often occurred in patients with metastatic colorectal cancer and ovarian cancer (up to 2% of patients), less often at other tumor sites. Infrequently (≥0.1- <1%), cases of the formation of fistulas of other sites (bronchopleural, urogenital, biliary) were recorded. Fistula formation is more often observed in the first 6 months of therapy with Avastin; however, it can occur both after 1 week and 1 year and later after the start of therapy. When a tracheoesophageal fistula or fistula of any localization of 4 degrees of severity occurs, Avastin therapy; should cancel. There is limited information on the continued use of the drug Avastin; in patients with fistulas of other sites. In the event of an internal fistula that does not penetrate the gastrointestinal tract, the question of discontinuing Avastin should be considered; patients who receive Avastin ;, the risk of bleeding, especially bleeding from the tumor, is increased. Drug Avastin; should be canceled if bleeding of 3 or 4 degrees of severity occurs according to the NCI-CTC classification. The overall incidence of bleeding 3-5 severity when using the drug Avastin; by all indications is 0.4-6.5%. Bleeding from the tumor or minor bleeding from the mucous membrane and skin (eg, nose bleeding) was most often observed. Nose bleeding of the first severity according to the NCI-CTC classification was observed most often, which lasted less than 5 minutes, resolved without medical intervention and did not require a regime change. dosing of the drug Avastin ;. The frequency of minor bleeding from the mucous membrane and skin depends on the dose of the drug.Less frequently, small bleeding of the gums or vaginal bleeding occurred. Abundant or massive pulmonary hemorrhage / hemoptysis was observed mainly in non-small cell lung cancer. Intake of antirheumatic / anti-inflammatory drugs, anticoagulants, prior radiation therapy, atherosclerosis, central tumor location, cavity formation before or during treatment are possible risk factors for pulmonary hemorrhage / hemoptysis, while statistically significant linkage with the development of bleeding has been established. Patients who recently had bleeding / hemoptysis (more than 2.5 ml of blood) should not receive the drug Avastin;. In patients with colorek gastrointestinal bleeding associated with a tumor, including rectal bleeding and melena. Rarely observed bleeding, incl. intracranial hemorrhages, in patients with metastatic lesions of the central nervous system or glioblastoma. It is necessary to monitor the symptoms of intracranial hemorrhages, if they occur, to discontinue therapy with Avastin; Avastin Drug; Caution should be exercised due to the lack of information on the safety profile of the drug in these patients. There was no increase in the incidence of bleeding grade 3 and higher in patients receiving the drug Avastin; and warfarin. Individual cases were reported, as well as a series of cases of serious adverse events on the part of the organ of vision (including infective endophthalmitis and other inflammatory diseases) after unregistered intravitreal administration of the drug Avastin ;. Some of these phenomena led to loss of visual acuity of varying degrees of severity, including persistent blindness. Drug Avastin; not intended for intravitreal administration. In patients who received Avastin ;, there was an increased incidence of arterial hypertension of all degrees of severity (up to 42.1%). According to all indications, the frequency of arterial hypertension of 3-4 severity grades 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 increased blood pressure is probablydepends on the dose of bevacizumab. Avastin; can be prescribed only to patients with pre-compensated arterial hypertension with further control of blood pressure. Information on the effect of the drug Avastin; in patients with uncontrolled arterial hypertension at the time of initiation of therapy is absent. In patients with arterial hypertension requiring drug therapy, it is recommended to temporarily discontinue therapy with Avastin; until normalization of blood pressure is achieved. In most cases, blood pressure normalization is achieved using standard antihypertensive drugs (ACE inhibitors, diuretics, and slow calcium channel blockers), selected individually for each patient. Cancel therapy with Avastin; or hospitalization was rarely required. Hypertensive encephalopathy, some fatal, was rarely observed. The risk of arterial hypertension associated with therapy with Avastin ;, does not correlate with the initial characteristics of the patient, concomitant disease or concomitant therapy. Therapy with Avastin; must be stopped in the absence of normalization of blood pressure, the development of hypertensive crisis or hypertensive encephalopathy. When treated with Avastin; isolated cases of posterior reversible encephalopathy, manifested by an 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 MRI). In the case of the development of posterior reversible encephalopathy, symptomatic therapy should be prescribed, blood pressure should be carefully monitored, and Avastin should be discontinued; Usually, resolution or improvement of symptoms occurs within a few days, however, some patients had neurological complications. The safety of the reappointment of the drug Avastin; in such patients not established. When treated with Avastin; in combination with chemotherapy, the incidence 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 cases of arterial thromboembolism was 3.8%. In the event of arterial thromboembolism, Avastin therapy; need to stop.A history of arterial thromboembolism or over 65 years of age is associated with an increased risk of arterial thromboembolism during treatment with Avastin ;. At treatment of such patients it is necessary to show care. During treatment by the drug Avastin; There is an increased risk of venous thromboembolism (PE, deep vein thrombosis, thrombophlebitis). The overall incidence of venous thromboembolism (deep vein thrombosis and pulmonary embolism) varies from 2.8% to 17.3%. Therapy with Avastin; it is necessary to stop when a life-threatening phenomenon occurs (4th severity) of venous thromboembolism, including pulmonary embolism, and if the severity of venous thromboembolism is ≤3, careful monitoring of the patient's condition should be performed. Chronic heart failure (CHF) occurred when using Avastin; by all indications, but mainly in metastatic breast cancer. Both an asymptomatic decrease in the left ventricular ejection fraction and CHF that required therapy or hospitalization were observed. 3.5 degrees of CHC and severity were observed in 3.5% of patients receiving Avastin ;. In patients receiving the drug Avastin; in combination with anthracycline drugs, the frequency of CHF 3 severity and higher did not differ from the available data in the treatment of metastatic breast cancer. The majority of patients showed improvement in symptoms and / or left ventricular ejection fraction with appropriate treatment. There is no history of CHF in patients with chronic heart failure Class II-IV according to NYHA classification. In most cases, CHF occurred in patients with metastatic breast cancer, treated with anthracyclines, radiation therapy to the chest area in history or with other risk factors for CHS. There is a need for caution when prescribing Avastin; in patients with a clinically significant cardiovascular disease in history, such as coronary heart disease or HSN. In patients who have not previously received anthracycline therapy with the drug Avastin; and anthracycline drugs were not observed to increase the frequency of CHF of any severity compared with monotherapy drugs anthracycline.CHF grade 3 and higher occurred more often in the Avastin treatment group; in combination with chemotherapy compared with chemotherapy alone, which is also consistent with other data obtained from patients with metastatic breast cancer and not receiving concomitant anthracycline therapy. Patients with diffuse large B-cell lymphoma with bevacizumab and doxorubicin in a cumulative dose of more than 300 mg / m2 there was an increase in the number of new cases of CHF. When comparing therapy with rituximab / cyclophosphamide / doxorubicin / vincristine / prednisone (R-CHOP) + bevacizumab and R-CHOP, the number of new cases did not differ, but was higher than that observed previously with doxorubicin therapy. The frequency of CHF was higher in the R-CHOP + group of bevacizumab. Avastin preparation; may adversely affect wound healing. Bevacizumab treatment should begin no less than 28 days after extensive surgery or with a full healing wound. With the development during treatment of complications associated with wound healing, the drug Avastin; must be temporarily canceled until the wound heals. The introduction of the drug Avastin; it is also necessary to temporarily discontinue in case of planned surgery. Rare cases of necrotizing fasciitis have been registered (including fatal cases) in patients treated with Avastin ;. This complication, as a rule, developed on the background of impaired wound healing, gastrointestinal perforation or fistula formation. If necrotizing fasciitis is detected, the drug Avastin; appropriate treatment should be canceled and immediately begun. Proteinuria was observed in 0.7-38% of patients receiving Avastin ;. In severity, proteinuria ranged from transient asymptomatic detection of traces of protein in the urine and in 1.4% of patients to nephrotic syndrome (proteinuria 4 degrees of severity). Proteinuria grade 3 is registered in 8.1% of patients who received the drug Avastin; for various reasons. Proteinuria was not associated with impaired renal function and rarely required discontinuation of therapy with Avastin ;. The risk of developing proteinuria is increased in patients with a history of arterial hypertension.Probably, grade 1 proteinuria depends on the dose of Avastin;. When grade 4 proteinuria develops, Avastin is a drug; need to cancel. Before and during therapy with Avastin; It is recommended to conduct urine analysis for proteinuria. In most cases, with proteinuria ≥2 g / day therapy with Avastin; temporarily suspended until the reduction of proteinuria <2 g / day. During therapy with Avastin; in combination with myelotoxic chemotherapy regimens, there was an increase in the incidence of severe neutropenia, febrile neutropenia, or infections with severe neutropenia (including cases of fatal outcome). Patients may experience an increased risk of developing infusion / hypersensitivity reactions. There is evidence of more frequent development of anaphylactic reactions and reactions of the anaphylactoid type in patients receiving the drug Avastin; in combination with chemotherapy, compared with patients who received only chemotherapy. Careful monitoring of the patient during and after administration of the drug Avastin is recommended ;. If an infusion reaction occurs, it is necessary to interrupt the infusion and take appropriate medical measures. Systematic premedication cannot guarantee the absence of infusion / hypersensitivity reactions. Cases of osteonecrosis of the jaw have been reported in cancer patients who received Avastin ;. Most of these patients received bisphosphonates in / in previously or as concomitant therapy; osteonecrosis of the jaw is an identified risk for bisphosphonates. Care must be taken with simultaneous or sequential use of the drug Avastin; and bisphosphonates in / in. Invasive dental procedures are also an identified risk factor. Before starting treatment with Avastin; a dental examination and appropriate preventive dental care should be carried out. If possible, avoid invasive dental procedures in patients who have previously received or are currently receiving IV bisphosphonates. Patients over 65 years of age: when prescribing Avastin; patients over the age of 65 have an increased risk of arterial thromboembolism (including the development of stroke,transient ischemic attack, myocardial infarction), leukopenia 3-4 severity and thrombocytopenia, as well as neutropenia (all severity), diarrhea, nausea, headache and fatigue compared with patients ≤65 years. Increased incidence of other adverse reactions associated with the use of the drug Avastin; (gastrointestinal perforations, complications associated with wound healing, arterial hypertension, proteinuria, CHF and bleeding) in patients over 65 years old compared with patients ≤65 years old. Disposal of unused medication or expired should be carried out in accordance with the requirements medical institutions. The impact on the ability to drive vehicles and control mechanisms Research on the effect of the drug on the ability to drive vehicles, mechanisms were not conducted. Patients who have such adverse events as syncope, drowsiness or visual impairment should refrain from driving vehicles, mechanisms.