Universal reference book for medicines
Product name: BEVACIZUMAB (BEVACIZUMAB)

Active substance: bevacizumab

Type: Antitumor drug.
Monoclonal antibodies
Composition, form of production and packaging
Concentrate for the preparation of solution for infusions is transparent or opalescent, colorless or light brown in color.
1 ml

Bevacizumab 25 mg

Excipients:?,? - trehalose dihydrate - 60 mg, sodium dihydrogen phosphate monohydrate - 5.8 mg, sodium hydrophosphate - 1.2 mg, polysorbate 20 - 0.4 mg, water d / and - up to 1 ml.

0.5 ml - glass bottles (1) - packings contour mesh (1) - packs cardboard.

4 ml - bottles of glass (1) - packs of cardboard.

16 ml - bottles of glass (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

Bevacizumab is a humanized recombinant hyperchimeric monoclonal antibody that selectively binds to the biologically active vascular endothelial growth factor (VEGF) and neutralizes it.
Bevacizumab inhibits the binding of the vascular endothelial growth factor to its 1 and 2 receptor receptors (Fit-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 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 the bevacizumab preparation 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 the bevacizumab drug was associated with dysplasia of the cartilaginous plate.

PHARMACOKINETICS

The pharmacokinetics of the bevacizumab preparation was studied after iv administration 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.
Bevacizumab distribution is characterized by low clearance, low volume of distribution in the central chamber (V c ) and prolonged T 1/2 , which allows to maintain the required therapeutic concentration of the drug in the plasma when administered once every 2-3 weeks.
The clearance of bevacizumab does not depend on the age of the patient.

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

Distribution

V c is 2.73 L and 3.28 L in women and men, respectively, which corresponds to V d of class G (IgG) immunoglobulins and;
other monoclonal antibodies. The volume distribution in the peripheral chamber (V p ) is 1.69 L and 2.35 L 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, V c is 20% more than in women.
Metabolism

After a single intravenous administration of 125 I-bevacizumab, its metabolic characteristics are similar to those of a natural IgG molecule that does not bind to VEGF.
Metabolism and excretion of bevacizumab corresponds to the metabolism and excretion 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. Binding of IgG to neonatal receptors to the crystallizing fragment of IgG (FcRn receptors) protects it from cellular metabolism and provides a long T 1/2 .
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 for women and 0.220 l / day for 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, T 1/2 for women is 18 days, and for men - 20 days.
Pharmacokinetics in special 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 V d and the 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
is not the main organ of metabolism and excretion of bevacizumab.
INDICATIONS

Metastatic colorectal cancer:

- in combination with chemotherapy based on fluoropyrimidine derivatives.

Locally recurrent or metastatic breast cancer:

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

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

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

Common and / or metastatic renal cell carcinoma:

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

Glioblastoma (grade IV glioma according to WHO classification):

- 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 the common (IIIB, IIIC and IV stages 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 VFGF 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.

DOSING MODE

Bevacizumab is administered only in / in the drip;
inject the drug intravenously!
Bevacizumab is not intended for intravitreal administration.

Bevacizumab is pharmaceutically incompatible with dextrose solutions.

The required amount of bevacizumab 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 IV infusion. If the first infusion is well tolerated, then the second infusion can be performed within 60 minutes. If the infusion is well tolerated within 60 minutes, all subsequent infusions can be carried out within 30 minutes. It is not recommended to reduce the dose of bevacizumab because of undesirable phenomena. If necessary, treatment with bevacizumab should be stopped completely or temporarily.
Standard dosing regimen

Metastatic colorectal cancer

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

It is recommended that bevacizumab be used until signs of disease progression or unacceptable toxicity.

As a second line of therapy: patients who were previously treated with bevacizumab after the first progression of the disease may continue treatment with bevacizumab if the chemotherapy regimen is changed:

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

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

Locally-recurrent or metastatic breast cancer (BC)

10 mg / kg once every 2 weeks as an IV infusion, long-term.

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

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

Bevacizumab is prescribed in addition to platinum-based chemotherapy (the maximum duration of chemotherapy is 6 cycles), then the administration of bevacizumab continues as monotherapy.
If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.
Recommended doses:

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

- 15 mg / kg once every 3 weeks as an intravenous infusion in addition to carboplatin-based chemotherapy.

Common and / or metastatic renal cell carcinoma

10 mg / kg once every 2 weeks as an IV infusion, long-term.

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

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

For the first time diagnosed, 10 mg / kg once every 2 weeks as an IV infusion in combination with radiotherapy and temozolomide for 6 weeks.
After a 4-week break, the administration of bevacizumab is resumed at a dose of 10 mg / kg every 2 weeks in combination with temozolomide. Temozolomide appointed 4-week cycles, duration of therapy with temozolomide - up to 6 cycles.
Further, the administration of bevacizumab is continued as monotherapy at a dose of 15 mg / kg once every 3 weeks.

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

In case of recurrent disease: 10 mg / kg once every 2 weeks as an IV infusion, prolonged.

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy 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 IV infusion in addition to carboplatin and paclitaxel (the maximum duration of chemotherapy is 6 cycles), then the administration of bevacizumab continues as monotherapy.
The total duration of therapy for bevacizumab is 15 months.
If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

With a recurrent disease:

- sensitive to platinum: 15 mg / kg once every 3 weeks as an IV infusion in combination with carboplatin and gemcitabine (6-10 cycles), then the administration of bevacizumab continues as monotherapy.

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

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

If there is evidence of disease progression or unacceptable toxicity, bevacizumab therapy should be discontinued.

Use in special patient groups

Children and teens

The safety and efficacy of bevacizumab in children and adolescents has not been established.

Patients of advanced age (over 65 years)

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

Patients with renal insufficiency

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

Patients with hepatic insufficiency

The safety and efficacy of bevacizumab in patients with hepatic insufficiency ns has been studied.

Instructions for use, handling and destruction

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

Bevacizumab does not contain an antimicrobial preservative, so it is necessary to ensure the sterility of the prepared solution and use it immediately.
If the preparation is not used immediately, the time and storage conditions of the prepared solution are the responsibility of the user. Store the prepared solution for a maximum of 24 hours at a temperature of + 2 ° C to + 8 ° C if dilution is carried out under 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 EFFECT

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 treated with 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 have a dose-dependent character.

Below are the adverse reactions of all severity grades according to the classification of the National Cancer Institute (NCI-CTC) found in patients treated with 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 (for example, palmar-plantar syndrome with capecitabine therapy and peripheral sensory neuropathy with paclitaxel or oxaliplatin therapy); However, we can not rule out the weighting of the condition with bevacizumab therapy. When using bevacizumab in combination with methylated liposomal doxorubicin, an increased risk of developing the palmar-plantar syndrome is possible.
On the part of the blood and lymphatic system: very often - febrile neutropenia, leukopenia, neutropenia, thrombocytopenia;
often - anemia, lymphocytopenia.
From the nervous system: very often - peripheral sensory neuropathy, dysgeusia, headache, dysarthria;
often - stroke, syncope, drowsiness.
From the side of the organ of vision : very often - visual impairment, increased lachrymation.

From the heart: often - chronic heart failure, supraventricular tachycardia.

From the side of blood vessels: very often - increased blood pressure;
often - arterial thromboembolism, deep vein thrombosis, hemorrhage, incl. pulmonary, intracranial, from the mucous membrane and skin, GIT and from the tumor.
From the respiratory system.
organs of the chest and mediastinum: very often - shortness of breath, nosebleeds, rhinitis; often - thromboembolism of the pulmonary artery (PE), hypoxia.
From the digestive tract: very often - anorexia, diarrhea, nausea, vomiting, constipation, stomatitis, rectal bleeding;
often - perforation of the digestive tract, intestinal obstruction, incl. obturation, abdominal pain, gastrointestinal disorders, pain in the rectum.
From the side of the liver and bile ducts: the frequency is unknown - perforation of the gallbladder.

From the skin and subcutaneous tissues: very often - exfoliative dermatitis, dry skin, discoloration of the skin;
often - palmar-plantar syndrome, inflammation of subcutaneous fat.
From the musculoskeletal and connective tissue: very often - arthralgia;
often - muscle weakness, myalgia, back pain.
From the kidneys and urinary tract: very often - proteinuria;
often - infection of the urinary tract.
On the part of genitals and mammary .zhelezy: very often - failure of ovarian function (amenorrhea lasting 3 months. Or more (concentration of follicle stimulating hormone (FSH)? 30 mIU / mL with a negative pregnancy test with determination of beta human chorionic gonadotropin (? -XGCH ) in serum), often - pain in the pelvis.
General disorders and at the injection site: very often - pain, including in the injection site, fatigue, increased fatigue, pyrexia, inflammation of the mucous membranes of various localization and often - lethargy, confusion, septicemia, abscesses, accession secondary infections, dehydration.
Laboratory and instrumental data:hyperglycemia, hypokalemia, hyponatremia, prolonged prothrombin time, INR increase, reduction of body weight.
Post-registration experience with bevacizumab
From the nervous system: rarely - back reversible encephalopathy syndrome; very rarely - hypertensive encephalopathy.
From the side of blood vessels: the frequency is unknown - renal thrombotic microangiopathy, clinically manifested by proteinuria.
The respiratory system, organs, thoracic and mediastinal disorders: often - dysphonia; the frequency is unknown - perforation of the nasal septum, pulmonary hypertension.
From the gastrointestinal tract: the frequency is unknown - gastroinstestinalnaya ulcer.
With the side of the liver and biliary tract:the frequency is unknown - perforation of the gallbladder.
With hand musculoskeletal and connective tissue frequency is unknown - the jaw osteonecrosis (mainly in patients receiving concomitant therapy with bisphosphonates or receiving bisphosphonate therapy earlier).
General disorders and at the injection site: rarely - necrotizing fasciitis usually on the background of impaired wound healing, gastrointestinal perforation or fistula formation; the frequency is unknown - hypersensitivity reactions, infusion reactions, with the following possible simultaneous manifestations: dyspnoea / difficulty breathing, "tides" / redness / rash, decreased or increased blood pressure, oxygen desaturation, chest pain, chills and nausea / vomiting.
Laboratory and instrumental data: frequency is unknown - hyperglycemia, hypokalemia, hyponatremia, prolonged prothrombin time, increasing INR.
CONTRAINDICATIONS

- increased sensitivity to bevacizumab or to any other component of the preparation, formulations based on Chinese hamster ovary cells or other recombinant human or approximate to human antibodies;
- Pregnancy and lactation;
- children's age till 18 years;

- renal and hepatic failure (efficacy and safety have not been established).
Precautions
In arterial thromboembolism; diabetes; the age of 65; congenital hemorrhagic diathesis and acquired coagulopathies; when taking anticoagulants for the treatment of thromboembolism prior bevacizumab; clinically significant cardiovascular disease (ischemic heart disease, or chronic heart failure history); hypertension; venous thromboembolism; wound healing; bleeding / hemoptysis; Gastrointestinal perforation in history; syndrome rear reversible encephalopathy; neutropenia; proteinuria.
PREGNANCY AND LACTATION

Use of the drug is contraindicated in pregnancy.
Women of childbearing age during treatment with bevacizumab and, at least, within 6 months after the end of treatment must use reliable methods of contraception.
Breastfeeding is not recommended during treatment with bevacizumab and, at least, within 6 months after the end of therapy with bevacizumab.
APPLICATION FOR FUNCTIONS OF THE LIVER

Do not use this drug in patients with renal insufficiency (efficacy and safety have not been established).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Do not use this drug to patients with hepatic failure (efficacy and safety have not been established).
APPLICATION FOR CHILDREN

Do not use this medication for children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS

Be wary of the drug in patients older than 65 years. Dose adjustment in patients over the age of 65 years is required.
SPECIAL INSTRUCTIONS

Perforation of the gastrointestinal tract and gall bladder
Bevacizumab can be carried out only under the supervision of a physician who is experienced in the use of antineoplastic therapy. Patients receiving the drug bevacizumab, there is an increased risk of perforation (GI) tract and gallbladder. Experienced severe GI perforation cases, including and fatal (at 0.2% -1% of all patients receiving bevacizumab). The clinical picture is characterized by perforations on the digestive tract, and severity varied depending on the sign of free gas at the abdomen radiography, which disappeared without any treatment, to the perforations with abdominal abscess and legal consequences. In some cases, there has been initial intraperitoneal inflammation of the gastric ulcer, tumor necrosis, diverticulitis or colitis associated with chemotherapy.The relationship between development intraperitoneal inflammation and gastrointestinal perforations and bevacizumab has not been established. With the development of gastrointestinal perforation with bevacizumab treatment should be discontinued.
Fistulas
With bevacizumab reported serious cases of the formation of fistulas, including cases of e death. Gastrointestinal fistulas occur most often in patients with metastatic colorectal cancer and ovarian cancer (up to 2% of patients), more rarely in other tumor localizations. Infrequently (0.1% - <1%) were recorded cases of fistula formation at other sites (bronchopleural, urogenital, biliary). Fistulas often occurs in the first 6 months of therapy with bevacizumab, but can occur both at 1 week and at 1 year and later after the start of therapy.
In the event of tracheo-esophageal fistula or fistula any location 4 severity bevacizumab therapy should be discontinued. There is limited information on the continuation of the use of bevacizumab in patients with fistulas of other locations. In the event of internal fistula does not penetrate into the blood, should consider discontinuation of bevacizumab.
bleeding
In patients receiving bevacizumab increased the risk of bleeding, particularly bleeding from the tumor. Bevacizumab should be canceled when bleeding occurs 3 or 4 severity classification NCI-CTC. The overall incidence of bleeding severity 3-5 when used for all indications bovatsizumaba is 0.4% -6.5%. Most often observed bleeding from a tumor or minor bleeding from the skin and mucosal (e.g., nasal bleeding).
Most often observed nosebleeds 1 severity classification NCI-CTC, which lasted less than 5 minutes, resolved without medical intervention and did not require changes in dosage regimen of bevacizumab. The frequency of small bleeding from mucous membranes and skin depends on the dose. Less commonly, there is a slight bleeding of the gums, or vaginal bleeding.
Heavy or massive pulmonary hemorrhage / hemoptysis were observed mainly in the non-small cell lung cancer. Admission antirheumatic / anti-inflammatory drugs, anticoagulants, prior radiotherapy, atherosclerosis, central tumor location, 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 (over 2.5 ml of blood) should not receive bevacizumab.
In patients with colorectal cancer are possible gastrointestinal bleeding associated with the tumor, including rectal bleeding and melena.
Rarely observed bleeding, including intracranial hemorrhage in patients with metastatic disease of the CNS or with glioblastoma.
It is necessary to monitor the symptoms of intracranial hemorrhage, in case of their occurrence cancel bevacizumab.
In patients with congenital bleeding diathesis, acquired coagulopathy or receiving full dose of anticoagulants on the thromboembolism before prescribing bevacizumab should be careful because of the lack of information on the safety profile of the drug in these patients. There was no increase incidence of bleeding Grade 3 or higher for patients receiving bevacizumab preparation and warfarin.
Violations by the organ of vision
Reported individual cases, as well as a series of cases of serious adverse events by organ of vision (including infectious endophthalmitis and other inflammatory diseases) after an unregistered! intravitreal injection of bevacizumab. Some of these events have led to the loss of visual acuity of varying severity, including persistent blindness. Bevacizumab is not intended for intravitreal injection.
Hypertension
In patients receiving bevacizumab observed increased incidence of hypertension of all degrees of severity (up to 26.47%). For all indications frequency hypertension 3-4 severity of NCI-CTC classification was 0.4% -17.9%; 4 severity (hypertonic crisis) occurred in 1% of patients.
Clinical safety data suggest that the incidence of high BP is likely to depend on the dose of bevacizumab. Bevacizumab can be assigned only to patients with pre-hypertension compensated with a further control of blood pressure. Information on the impact of bevacizumab in patients with uncontrolled hypertension at the time of initiation of therapy available. In patients with hypertension requiring drug therapy, it is recommended to temporarily discontinue therapy with bevacizumab to achieve normalization of blood pressure.
In most cases, normalization of blood pressure is achieved using standard antihypertensive agents (ACE inhibitor, diuretics and blockers "slow" calcium channel) selected individually for each patient. Cancel bevacizumab or hospitalization were required rarely.
Cases of hypertensive encephalopathy, some with the legal outcome is very rarely observed. The risk of hypertension associated with bevacizumab therapy ns correlated with the original characteristics of the patient, concurrent disease or concomitant therapy.
Bevacizumab therapy should be discontinued in the absence of normalization of blood pressure, the development of hypertensive crisis or hypertensive encephalopathy.
Rear reversible encephalopathy
When bevacizumab registered isolated cases of reversible encephalopathy syndrome rear manifested seizures, headache, mental disorders, visual impairment, lesion of the visual centers of the cerebral cortex, with or without hypertension and other symptoms. Diagnosis can be confirmed by brain imaging techniques (preferably with MRI). In the case of posterior reversible encephalopathy syndrome should appoint a symptomatic therapy, carefully monitor blood pressure and discontinuation of bevacizumab. Typically, the resolution or improvement of symptoms occurs within a few days, but some patients experienced neurological complications. reappointment of bevacizumab safety in these patients has not been established.
Arterial and venous thromboembolism
When bevacizumab therapy in combination with chemotherapy frequency arterial thromboembolism, including stroke, transient ischemic attack, myocardial infarction and other phenomena of arterial thromboembolism was higher than the appointment chemotherapy alone. The overall incidence of cases of arterial thromboembolic events was 3.8%. In the event of arterial thromboembolism with bevacizumab therapy should be discontinued. Arterial thromboembolism or age greater than 65 years is associated with an increased risk of arterial thromboembolic events during treatment with bevacizumab. When treating such patients need to exercise caution.
During treatment with bevacizumab have an increased risk of venous thromboembolism (pulmonary embolism, deep vein thrombosis, thrombophlebitis). The overall incidence of venous thromboembolism (deep vein thrombosis and pulmonary embolism) ranges from 2.8% to 17.3%.
Treatment with bevacizumab should be stopped in case of life-threatening events (Grade 4 severe) venous thromboembolism, including pulmonary embolism, and in the severity of venous thromboembolism? 3 should be carefully monitoring the patient's condition.
Chronic heart failure
Chronic heart failure (CHF) occurred when bevacizumab for all indications, but mainly in metastatic breast cancer. Observed both asymptomatic decrease in left ventricular ejection fraction and heart failure, which required treatment or hospitalization.
CHF Grade 3 or higher was observed in 3.5% of patients receiving bevacizumab drug. In patients receiving bevacizumab in combination with a number of anthracycline drugs, CHF 3 frequency and severity above does not differ from the data available in the therapy of metastatic breast cancer. The majority of patients had improvement of symptoms and / or left ventricular ejection fraction with appropriate treatment.
Data on the risk of CHF in patients with heart failure class II-IV according to the classification of the New York Heart Association (NYHA) in the history of no. B. .Most cases XCN occurred in patients with metastatic breast cancer receiving anthracycline therapy, radiation therapy to the chest area with a history or other risk factors for heart failure development.
Caution must be exercised in the appointment of bevacizumab in patients with clinically significant cardiovascular disease in history, such as coronary artery disease or heart failure.
Patients who did not receive therapy with anthracyclines earlier, when bevacizumab and preparations anthracyclines no increase in frequency of any severity of CHF in comparison with monotherapy with anthracyclines. 3 CHF severity and occurred more often higher in the group with bevacizumab therapy in combination with chemotherapy compared to chemotherapy alone, and another which corresponds to the data obtained in patients with metastatic breast cancer and not receiving concomitant therapy with anthracyclines.
Patients with diffuse large-cell lymphoma with bevacizumab therapy and a cumulative doxorubicin dose of 300 mg / m 2there was an increase in new cases of heart failure. When compared rituximab / cyclophosphamide / doxorubicin / vincristine / prednisone (R-CHOP) + bevacizumab and R-CNOP number of new cases was not different, but it was higher than that observed previously with doxorubicin therapy. CHF rate was higher in the group R-CHOP + bevacizumab.
Wound healing
Bevacizumab may adversely affect the wound healing. Bevacizumab treatment should be started at least 28 days after major surgery or complete healing of surgical wounds. With the development in the treatment of complications associated with wound healing, bevacizumab is necessary to temporarily suspend until complete healing of the wound. Introduction of bevacizumab also need to temporarily stop in the case of elective surgery.
Necrotizing fasciitis
Registered rare cases of necrotizing fasciitis (including fatal) in patients treated with bevacizumab. This phenomenon is generally developed on the background of wound healing disorders, gastrointestinal perforation or the formation of fistulas.
In case of necrotizing fasciitis bevacizumab should be withdrawn and immediately started
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