2010/06/24

Avastin

Composition, structure and packing

Concentrate for solution for infusion is transparent or opalescent, colorless or light brown in color.

1 ml 1 vial. bevacizumab 25 mg 100 mg.

Excipients: α, α-trehalose dihydrate, sodium dihydrogen monohydrate, disodium phosphate anhydrous, polysorbate 20, water d / and.

Concentrate for solution for infusion is transparent or opalescent, colorless or light brown in color.

1 ml 1 vial. bevacizumab 25 mg - 400 mg.

Excipients: α, α-trehalose dihydrate, sodium dihydrogen monohydrate, disodium phosphate anhydrous, polysorbate 20, water d / and.

Clinico-pharmacological group: The antitumor drug. Monoclonal antibodies.

Pharmacological action

The antitumor drug, is a recombinant giperhimernoe (humanised, approximate to the human) monoclonal antibody that selectively binds to biologically active vascular endothelial growth factor (VEGF) and neutralize it. Avastin inhibits the binding of VEGF to its receptors on the surface of endothelial cells, which leads to a decrease in vascularization and inhibition of tumor growth. Bevacizumab contains a fully human skeletal regions with defining complementary segment giperhimernogo mouse antibodies, which bind to VEGF. Bevacizumab receive recombinant DNA technology in the system for the expression provided by the ovarian cells of Chinese hamster. Bevacizumab is composed of 214 amino acids and a molecular mass of about 149 000 daltons. The introduction of bevacizumab leads to suppression of metastatic disease progression and reduce microvascular permeability in various human tumors, including cancer of the colon, breast, pancreas and prostate.

Metastatic colorectal cancer

Avastin in combination with irinotecan, 5-fluorouracil and leucovorin (IFL) as first-line treatment in patients with metastatic colorectal cancer significantly improves overall survival in all subgroups of patients regardless of age, sex, general condition, location of primary tumor, number of affected organs and duration of metastatic disease. Adding Avastin to IFL chemotherapy increases the survival time without progression of the disease, the overall frequency response and duration of response to treatment.

In the appointment of Avastin (5 mg / kg of body weight every 2 weeks) in combination with 5-fluorouracil and leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer and the presence of contraindications for the therapy of irinotecan observed: higher frequency of objective response to treatment, a statistically significant increase in progression-free survival and a tendency to increase overall survival compared with the appointment of only chemotherapy (5-FU/LV).

In the appointment of Avastin (7.5 mg / kg of body weight every 3 weeks) combined with oral capecitabine and oxaliplatin in / (XELOX) or the appointment of Avastin (5 mg / kg every 2 weeks) in combination with leucovorin and 5-fluorouracil bolus, and then 5-fluorouracil infusion and oxaliplatin in / (FOLFOX-4) was statistically significant increase in progression-free survival compared with chemotherapy appointment only.

In the appointment of Avastin (10 mg / kg of body weight every 2 weeks) in combination with leucovorin and 5-fluorouracil bolus and then infusion, and oxaliplatin in / (FOLFOX-4) patients previously treated with therapy (second line therapy), with advanced colorectal cancer was statistically significant increase in total survival, progression-free survival and a higher incidence of objective response compared with the appointment of only chemotherapy.

Locally recurrent or metastatic breast

Avastin (10 mg / kg of body weight every 2 weeks) in combination with paclitaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer significantly increases progression-free survival and objective response rate in comparison with the appointment of chemotherapy alone.

The widespread inoperable, metastatic or recurrent non small cell lung cancer lung neploskokletochny

Avastin (15 mg / kg every 3 weeks) in combination with chemotherapy drugs based on platinum (carboplatin and paclitaxel / v) as first-line therapy in patients with non small cell lung neploskokletochnym lung cancer significantly improves overall survival, the period of survival without disease progression and objective response rate compared with the appointment of chemotherapy alone.

Avastin (7.5 mg / kg or 15 mg / kg every 3 weeks) in combination with chemotherapy drugs based on platinum (cisplatin and gemcitabine / v) as first-line therapy in patients with non small cell lung neploskokletochnym lung cancer significantly increases progression-free survival period disease and objective response rate compared with the appointment chemotherapy alone. Distribution and / or metastatic renal cell cancer Avastin (10 mg / kg every 2 weeks) in combination with interferon alfa-2a (9 million IU 3 times weekly) as first-line therapy in patients with advanced and / or metastatic renal cell cancer significantly increases the period of survival without disease progression and objective response rate in comparison with the appointment of only interferon alfa-2a.

Pharmacokinetics

If i / in the introduction of bevacizumab in doses ranging between 1 and 10 mg / kg / body weight within 90 minutes of its pharmacokinetics were linear.

Distribution

With the introduction of bevacizumab 1 day a week, every 2 weeks or every 3 weeks at doses of 1 to 10 mg / kg to Vd is 2.66 L for women and 3.25 liter - for men.

Metabolism

After a single in / to the introduction 125I-bevacizumab his metabolic characteristics similar to those of the natural molecule IgG.

Withdrawal

Bevacizumab clearance was 0.207 l / day for women and 0.262 l / day - for men. Vd and clearance correspond to the initial T1 / 2, is 1.4 days, and end-T1 / 2, is 20 days for women and 19 days for men. This T1 / 2 corresponds to the final T1 / 2 of the human endogenous IgG, which is 18-23 days. After adjusting doses, taking into account body mass clearance of bevacizumab in men above 26%, than women. Patients with low albumin (≤ 29 g / dl) and high levels of alkaline phosphatase (≥ 484 IU / L) (both are markers of disease severity), bevacizumab clearance value of approximately 20% higher than in patients with mean laboratory parameters.

Pharmacokinetics in special clinical situations

There were no significant differences in the pharmacokinetics of bevacizumab, depending on age. Safety and efficacy of bevacizumab in children and adolescents has not been studied. Safety and efficacy of bevacizumab in patients with renal or hepatic insufficiency has not been studied.

Statement
metastatic colorectal cancer: in combination with chemotherapy based on derivatives ftorpirimidina;
locally recurrent or metastatic breast cancer: as a first line therapy in combination with paclitaxel;
widespread inoperable, metastatic or recurrent non small cell lung cancer neploskokletochny light: as a first line therapy in addition to chemotherapy drugs based on platinum;
distribution and / or metastatic renal cell carcinoma: as first-line therapy in combination with interferon alfa-2a.

Dosage regimen

Avastin is introduced only in / drip; enter the drug / a jet can not!

Needed Avastin diluted to a total volume of 100 ml of sterile, apyrogenic 0.9% sodium chloride solution in compliance with the rules of asepsis. Concentration bevacizumab in prepared solution must be within 1.4-16.5 mg / ml. The initial dose of the drug is introduced into / in as infusion within 90 minutes after the chemotherapy, subsequent doses can be introduced before or after chemotherapy. When the first infusion is well tolerated, the second infusion can be carried out within 60 minutes. If the infusion within 60 minutes is well tolerated, all subsequent infusions can be carried out within 30 minutes. It is not recommended to reduce the dose of bevacizumab because of adverse events. If necessary, treatment drug Avastin should be completely or temporarily stop.

Metastatic colorectal cancer
As a first-line therapy: 5 mg / kg 1 time in 2 weeks or 7.5 mg / kg 1 every 3 weeks in the form of in / infusion, long time.
As a second-line treatments: 10 mg / kg 1 time in 2 weeks or 15 mg / kg 1 every 3 weeks in the form of in / infusion, long time.

If signs of disease progression therapy Avastin should be discontinued.

Locally recurrent or metastatic breast

The drug is prescribed in doses of 10 mg / kg 1 every 2 weeks or 15 mg / kg 1 every 3 weeks in the form of in / infusion, long time. If signs of disease progression therapy Avastin should be discontinued.

The widespread inoperable, metastatic or recurrent non small cell lung cancer lung neploskokletochny

Avastin is prescribed in addition to chemotherapy for platinum-based drugs (the maximum duration of chemotherapy, 6 cycles), then receiving Avastin continues as monotherapy. If signs of disease progression therapy Avastin should be discontinued. Recommended dosage: - 7.5 mg / kg 1 every 3 weeks in the form of / in addition to the infusion of chemotherapy based on cisplatin. - 15 mg / kg 1 every 3 weeks in the form of / in addition to the infusion of chemotherapy based on carboplatin.

Distribution and / or metastatic renal cell carcinoma

The drug is prescribed in doses of 10 mg / kg 1 time in 2 weeks in the form of in / infusion, long time. If signs of disease progression therapy Avastin should be discontinued. Elderly patients (over 65 years) dose adjustment is required.

Instructions for use, handling and destruction of the drug

Before applying the solution should be inspected for the presence of mechanical inclusions and changes color. 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 drug is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user. Store prepared solution can be not more than 24 hours at a temperature of 2 ° to 8 ° C, if breeding is done under controlled and validated aseptic conditions.

Chemical and physical stability of the prepared solution (in 0.9% sodium chloride solution), lasts for 48 hours at a temperature of 2 ° to 30 ° C. Unused solution remaining in the vial, destroy, because it does not contain preservatives.

Side effect

The most serious adverse reactions: gastrointestinal perforation, hemorrhage, including pulmonary hemorrhage / hemoptysis (more common in patients with non small cell lung neploskokletochnym lung cancer), arterial thromboembolism. Increased blood pressure and the development of proteinuria, probably has a dose-dependent nature. In patients treated with Avastin only, the most frequently observed: increased blood pressure, weakness or asthenia, diarrhea, nausea and abdominal pain. The following adverse reactions of varying severity, occurring in patients receiving Avastin as monotherapy or in combination with chemotherapy.

Since the cardiovascular system: hypertension, arterial thromboembolism (including myocardial infarction, stroke, transient ischemic attack and other arterial embolism), deep vein thrombosis, chronic heart failure, supraventricular tachycardia, bleeding. On the part of the hemopoietic system: leukopenia, neutropenia, febrile neutropenia, anemia, and thrombocytopenia. On the part of the digestive system: taste perversion, abdominal pain, diarrhea, constipation, rectal bleeding, stomatitis, bleeding gums, gastrointestinal perforation, bowel obstruction, nausea, vomiting. On the part of the respiratory system: pulmonary thromboembolism, hypoxia, epistaxis, dyspnea, rhinitis. Dermatological reactions: palmar-plantar syndrome, dry skin, exfoliative dermatitis, skin discoloration. On the part of the nervous system: taste perversion, anorexia, syncope, stroke, headache, drowsiness, peripheral sensory neuropathy. On the part of the organ of vision: the violation of visual function. Disorders of laboratory tests grade 3 and 4 in accordance with the criteria of the National Cancer Institute (NCI-CTC), was observed in patients receiving Avastin with or without chemotherapy: hyperglycemia, decrease in hemoglobin levels, hypokalemia, hyponatremia, leukopenia, neutropenia, thrombocytopenia, proteinuria, increased prothrombin time, increased INR. Post marketing surveillance often: dysphonia. Rare: reversible late leukoencephalopathy syndrome, including an epileptic seizure, headache, mental disturbances, visual disturbances, damage to the visual centers of the cerebral cortex, hypertension. Very rare: nasal septum perforation; hypertensive encephalopathy (in some cases fatal). The frequency of occurrence is unknown: pulmonary hypertension.

Contraindications
metastatic involvement of the CNS;
renal and hepatic failure (effectiveness and safety have not been established);
Pregnancy
breastfeeding;
children's age (efficacy and safety have not been established);
Hypersensitivity to bevacizumab or to any other component, drugs based on Chinese hamster ovary cells or other recombinant human, or close to human antibodies.

Precautions should be prescribed medication for hypertension, arterial thromboembolism, patients older than 65 years in the healing of wounds, bleeding, hemoptysis, hemorrhagic diathesis in congenital and acquired coagulopathy when administered in high doses of anticoagulants, with perforation of the gastrointestinal tract, clinically significant cardiovascular disease or congestive heart failure, a history of neutropenia, proteinuria, late reversible leukoencephalopathy syndrome.

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding). Men and women of childbearing age during treatment with Avastin and at least within 6 months after treatment is necessary to use reliable methods of contraception. Feeding with breast milk is not recommended for at least 6 months after treatment Avastin.

Application for violations of liver function

The drug is contraindicated in hepatic failure (effectiveness and safety not established).

Application for violations of renal function

The drug is contraindicated in renal failure (efficacy and safety not established).

Cautions

Treatment Avastin can be done only under the supervision of a physician with experience in the use of antineoplastic therapy. Patients receiving Avastin, an increased risk of perforation of the digestive tract. There were severe cases of gastrointestinal perforation with peritonitis (including fatal).

The clinical picture of gastrointestinal perforations differed in severity, and ranged from signs of free gas in the X-ray of the abdominal cavity, which disappeared without treatment, up to perforation with abdominal abscess and fatal. In some cases there was an initial abdominal inflammation of the gastric ulcer, tumor necrosis, diverticulitis or colitis associated with chemotherapy. Relationship between the development of abdominal inflammation and perforation of the gastrointestinal tract with the reception of Avastin is not installed. However, caution must be exercised in the treatment of Avastin in patients with symptoms of abdominal inflammation. With the development of perforation treatment Avastin should be stopped. Avastin may interfere with wound healing.

Bevacizumab therapy should not begin earlier than 28 days after surgery or until complete healing of surgical wounds. With the development during the treatment of complications associated with wound healing, Avastin is necessary to temporarily lift until the wound heals.

Receiving Avastin is as necessary to temporarily stop in the event of a planned surgical intervention. In patients treated with Avastin, was an increased incidence of arterial hypertension. Clinical safety data suggest that the incidence of BP increase is likely to depend on the dose of bevacizumab. Avastin may be appointed only for patients with previously compensated arterial hypertension and further control of BP.

Patients with hypertension requiring drug therapy, it is recommended to temporarily stop Avastin therapy to achieve adequate control of BP. Normalization of blood pressure achieved with the help of ACE inhibitors, diuretics and calcium channel blockers. Receiving Avastin should be discontinued in the absence of normalization of BP, the development of hypertensive crisis or hypertensive encephalopathy. The risk of developing proteinuria was elevated in patients with arterial hypertension in history. It is possible that a degree of proteinuria depends on the dose of Avastin. Before and during therapy Avastin recommended urine test for proteinuria. Proteinuria was not associated with impaired renal function, proteinuria 4 levels (nephrotic syndrome) are rare. With the development of proteinuria 4 degrees Avastin should be abolished.

Patients receiving Avastin increased risk of bleeding, especially related to the tumor. Avastin should be revoked in the event of bleeding 3 or 4 severity. In patients with congenital hemorrhagic diathesis, acquired coagulopathy or receiving a full dose of anticoagulants on the thromboembolism, before the appointment of Avastin should be cautious due to the lack of information about the safety profile of the drug in such patients. There were no increase in the frequency of bleeding 3 severity and higher in patients treated with Avastin and warfarin in full dosage in connection with the occurrence of venous thrombosis.

Patients with non small cell lung lung cancer receiving Avastin, are at increased risk of serious, and in some cases, fatal pulmonary hemorrhage / hemoptysis. Patients who had hemorrhage / hemoptysis (more than 2.5 ml of blood) in history, should not receive Avastin. Receiving antirheumatic / anti-inflammatory drugs, anticoagulants, prior radiation therapy, atherosclerosis, central location of tumor formation of the cavity before or during treatment are possible risk factors for pulmonary hemorrhage / hemoptysis, with statistically significant correlation with these symptoms of bleeding proved only for squamous cell cancer the lung. Rarely bleeding during other types of tumors (hepatoma with metastatic CNS sarcoma with necrosis of the hip).

In patients with colorectal cancer may be bleeding gastrointestinal tract associated with the tumor, including rectal bleeding and melena. In 20-40% of patients were observed mucous and skin bleeding. Most often observed nosebleeds, not exceeding 1 severity, duration of less than 5 minutes. Nasal bleeding stopped without medical intervention and did not require changes to treatment Avastin. Fewer bleeding gums, or vaginal bleeding.

In therapy Avastin in combination with chemotherapy rates of arterial thromboembolic events including stroke, transient ischemic attack and myocardial infarction was higher than in the appointment of chemotherapy alone. Arterial thromboembolism, or age older than 65 years is associated with an increased risk of arterial thromboembolism during treatment with Avastin. When treating such patients should be treated with caution.

In the event of arterial thromboembolism Avastin therapy should be discontinued. During treatment with Avastin is an increased risk of venous thromboembolism (pulmonary embolism, deep vein thrombosis, thrombophlebitis).

Avastin therapy should be stopped when a life-threatening pulmonary embolism (4 severity), while the severity ≤ 3 should be carefully monitored. In therapy Avastin recorded isolated cases of reversible leukoencephalopathy later. The diagnosis can be confirmed by imaging techniques of the brain. In the case of complications should appoint a symptomatic therapy, carefully monitor blood pressure and cancel bevacizumab. Safety reappointment of Avastin in these patients is not installed.

In most cases, congestive heart failure occurred in patients with metastatic breast cancer receiving anthracycline therapy and / or radiation therapy to the chest in history, as well as other risk factors for developing congestive heart failure, such as coronary heart disease or concomitant therapy cardiotoxicity . Observed as an asymptomatic decrease in left ventricular ejection fraction and congestive heart failure that required treatment or hospitalization. Caution must be exercised in the appointment of Avastin to patients with clinically significant cardiovascular disease or congestive heart failure in history.

In therapy Avastin reported cases of fistula formation, including cases with fatal consequences. GI Fistulas occur most often in patients with metastatic colorectal cancer, less frequently in other tumor. Rarely reported cases of fistula formation at other sites (broncho-pleural, urogenital, biliary). Education fistula occurs more frequently in the first 6 months of therapy Avastin, but may occur as 1 week and 1 year later and after initiation of therapy. Avastin therapy should be repealed in the event of the tracheo-ezofagealnogo fistula or fistula of any location 4 degrees of severity. In the event of internal fistula not penetrating into the gastrointestinal tract, the abolition of Avastin solved individually.

In therapy Avastin in combination with chemotherapy regimes myelotoxicity observed increase in the frequency of severe neutropenia, febrile neutropenia or infection with severe neutropenia (including fatal cases). In appointing the Avastin patients older than 65 years there is a heightened risk of arterial thromboembolic events (including the development of stroke, transient ischemic attack, myocardial infarction), 3-4 leukopenia and thrombocytopenia severity and neutropenia (all degrees of severity), diarrhea, nausea, headache and asthenia. Increasing incidence of other adverse reactions associated with the use of Avastin, in elderly patients were observed.

Overdose

Symptoms: the appointment of bevacizumab to a maximum dose of 20 mg / kg in a few patients noted severe migraine. In case of overdose may strengthen the above side effects.

Treatment: No specific antidote. Spend symptomatically.

Drug Interactions

Effect of anticancer drugs on the pharmacokinetics of Avastin have been reported clinically significant effect on the distribution of Avastin to chemotherapy in the joint application. Clearance of bevacizumab did not differ in patients treated with Avastin only, and in patients treated with Avastin in combination with IFL (in bolus mode). The effect of other chemotherapy drugs (5-FU-LV, carboplatin, paclitaxel, doxorubicin or capecitabine) for the clearance of bevacizumab is considered to be clinically insignificant.

Impact of Avastin on the pharmacokinetics of other anticancer drugs Avastin does not have any significant effect on the pharmacokinetics of irinotecan and its active metabolite (SN38); capecitabine and its metabolites, and oxaliplatin (determined by the free and total platinum level) interferon alfa-2a, cisplatin. Reliable statistics on the impact of Avastin on the pharmacokinetics of gemcitabine not. With the combined use of warfarin (treatment of venous thrombosis) and Avastin increased the frequency of serious bleeding were observed. With Avastin (10 mg / kg 1 time in 2 weeks) in combination with sunitinibom (50 mg daily) in patients with metastatic renal cell carcinoma reported cases of microangiopathic hemolytic anemia (ICAA).

MAGA is a subgroup of hemolytic anemia, which can occur by fragmentation of erythrocytes, cell anemia and thrombocytopenia. Some patients additionally observed neurological disorders, elevated levels of creatinine, arterial hypertension, including hypertensive crisis. These symptoms were reversible after discontinuation of therapy, and bevacizumab sunitinibom. Safety and efficacy of Avastin in combination with radiotherapy has not been established. Pharmaceutical Pharmaceutical interaction is incompatible with dextrose.

Terms and Conditions of storage

The drug should be kept in the dark, away from children at a temperature of 2 ° to 8 ° C Do not freeze.

Shelf life - 2 years. The drug is not used beyond the expiration date indicated on the package.


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