Avastin, 400 mg/16 ml

Pharmacodynamics

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

Bevacizumab contains fully human framework sites with complement-defining regions of a hyperchimeric mouse antibody that 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.

The administration of bevacizumab leads to suppression of metastatic disease progression and reduction of microvascular permeability in various human tumors, including colorectal, breast, pancreatic and prostate cancers.

Preclinical safety data

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

Avastin® has been observed to have embryotoxic and teratogenic effects when administered to animals.

In actively growing animals with open growth areas, the use of Avastin® was associated with cartilage plate dysplasia.

Pharmacokinetics

The pharmacokinetics of Avastin® were 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, are described by a two-chamber model.

The distribution of Avastin® is characterized by low clearance, low central chamber volume distribution (V_c) and a long half-life (T_1/2), which allows the drug to maintain the required therapeutic plasma concentration when given once every 2-3 weeks.

The clearance of bevacizumab is independent of patient age. Clearance of bevacizumab is 30% higher in patients with low albumin levels and 7% higher in patients with a large tumor mass compared to patients with average values of albumin and tumor mass.

The distribution

V_c is 2.73 L and 3.28 L in women and men, respectively, which is consistent with the distribution volume of IgG and other monoclonal antibodies. The peripheral chamber distribution volume (V_p) is 1.69 L and 2.35 L in women and men, respectively, when bevacizumab is administered with other antitumor drugs. After adjusting the dose for body weight, V_c is 20% higher in men than in women.

Metabolism

After a single intravenous injection of ¹²⁵I-bevacizumab, its metabolic characteristics are similar to those of the natural IgG molecule, which does not bind to VEGF. The metabolism and excretion of bevacizumab corresponds to that of endogenous IgG, i.e., it is mainly by proteolytic catabolism in all cells of the body, including endothelial cells, rather than 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 long-lasting T_1/2.

Elevation

The pharmacokinetics of bevacizumab at doses ranging from 1.5 to 10 mg/kg per week are linear.

The clearance of bevacizumab is 0.188 L/day in women and 0.220 L/day in men. After adjusting the dose for body weight, bevacizumab clearance in men is 17% higher than in women. According to the dual-chamber model, the T_1/2 for women is 18 days and 20 days for men.

Pharmacokinetics in special patient groups

Patients older than 65

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

Children and adolescents

Limited data are available on the pharmacokinetics of bevacizumab in children and adolescents. Available data suggest that there is no difference between V_d and bevacizumab clearance in pediatric, adolescent, and adult patients with solid tumors.

Patients with renal or hepatic impairment

The safety and efficacy of bevacizumab in patients with renal or hepatic impairment have not been studied because the kidneys and liver are not the primary organs of metabolism and excretion of bevacizumab.

Indications

Cancer

Metastatic colorectal cancer:

• in combination with chemotherapy based on fluoropyrimidine derivatives.

Locally recurrent or metastatic breast cancer:

• as first-line therapy in combination with paclitaxel.

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

• as first-line therapy in addition to platinum-based chemotherapy.

Spread and/or metastatic renal cell cancer:

• as first-line therapy in combination with interferon alfa-2a.

The glioblastoma (glioma of grade IV malignancy according to the 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 relapsed glioblastoma or disease progression.

Epithelial cancer of the ovary, fallopian tube and primary peritoneal cancer:

• as first-line therapy in combination with carboplatin and paclitaxel for advanced (FIGO stage IIIB, IIIC, and IV) epithelial ovarian, fallopian tube, and primary peritoneal cancer;
• in combination with paclitaxel or topotecan or pegylated liposomal doxorubicin for recurrent, platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancer in patients who have received no more than two prior chemotherapy regimens.

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Active ingredient

Bevacizumab

Composition

Active ingredient:

Bevacizumab 400 mg.

Associates:

α,α-trehalose dihydrate – 960 mg,

sodium dihydrophosphate monohydrate – 92.8 mg,

Sodium hydrophosphate anhydrous – 19.2 mg,

Polysorbate 20 – 6.4 mg,

water d/i – 16 ml.

How to take, the dosage

Avastin® should only be given as an IV drip; it should not be given by IV jetting!

Avastin® is not intended for intravitreal administration.

Avastin® is pharmaceutically incompatible with dextrose solutions.

The necessary amount of Avastin® is diluted to the required volume with 0.9% sodium chloride solution observing the rules of asepsis. The concentration of bevacizumab in the prepared solution should range from 1.4-16.5 mg/ml.

The initial dose of the drug is administered by IV infusion for 90 minutes. If the first infusion is well tolerated, a second infusion may be given within 60 minutes. If the infusion within 60 min is well tolerated, all subsequent infusions may be given within 30 min.

It is not recommended to decrease the dose of bevacizumab due to adverse events. Avastin® treatment should be discontinued completely or temporarily if necessary.

The standard dosing regimen

Metastatic colorectal cancer

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

The therapy with Avastin® is recommended until signs of disease progression or unacceptable toxicity.

As second-line therapy: Patients who were previously treated with Avastin® after initial disease progression may continue treatment with Avastin® if the chemotherapy regimen is changed:

• If disease progresses after first-line therapy that included Avastin®: 5 mg/kg once every 2 weeks or 7.5 mg/kg once every 3 weeks as an IV infusion, long-term;
• in disease progression after first-line therapy that did not include Avastin®: 10 mg/kg once every 2 weeks or 15 mg/kg once every 3 weeks as an IV infusion, long-term.

Locally recurrent or metastatic breast cancer

The drug is administered at a dose of 10 mg/kg once every 2 weeks as an IV infusion, long-term.

Avastin® therapy should be discontinued if there are signs of disease progression or unacceptable toxicity.

Inoperable, metastatic or recurrent non-small cell lung cancer

Avastin® is administered in addition to chemotherapy on the basis of platinum medications (maximum duration of chemotherapy is 6 cycles), further Avastin® administration is continued as monotherapy. In case of signs of disease progression or unacceptable toxicity the therapy by Avastin® should be stopped.

Recommended doses:

• 7.5 mg/kg once every 3 weeks as an IV infusion in addition to cisplatin-based chemotherapy;
• 15 mg/kg once every 3 weeks as an IV infusion in addition to carboplatin-based chemotherapy.

Spread and/or metastatic renal cell cancer

The drug is administered at a dose of 10 mg/kg once every 2 weeks as an IV infusion, long-term.

Avastin® therapy should be discontinued if there are signs of disease progression or unacceptable toxicity.

Glioblastoma (WHO grade IV malignancy)

In newly diagnosed disease: 10 mg/kg once every 2 weeks as an IV infusion in combination with radiotherapy and temozolomide, for 6 weeks. After 4-week break Avastin® administration is resumed in dose of 10 mg/kg once per 2 weeks in combination with temozolomide. Temozolomide is administered in 4-week cycles, temozolomide therapy duration is up to 6 cycles. Then Avastin is continued as monotherapy at a dose of 15 mg/kg once every 3 weeks. In case of signs of disease progression or unacceptable toxicity the treatment with Avastin® should be stopped.

In case of recurrent disease: 10 mg/kg once every 2 weeks as an IV infusion, long-term. If there are signs of disease progression or unacceptable toxicity, Avastin® therapy should be discontinued.

Epithelial ovarian cancer, fallopian tube and primary peritoneal cancer

As first-line therapy: 15 mg/kg once in 3 weeks as an IV infusion in addition to carboplatin and paclitaxel (maximum duration of chemotherapy 6 cycles), further Avastin® administration is continued as monotherapy. The total duration of therapy with Avastin® is 15 months. In case of signs of disease progression or unacceptable toxicity the therapy with Avastin® should be discontinued.

In recurrent disease:

• sensitive to platinum drugs – 15 mg/kg once every 3 weeks as an IV infusion in combination with carboplatin and gemcitabine (6-10 cycles), then Avastin® is continued as monotherapy. If there are signs of disease progression or unacceptable toxicity Avastin® therapy should be discontinued.
• Platinum-resistant – 10 mg/kg once per 2 weeks as an IV infusion in combination with one of the following drugs: paclitaxel, topotecan (if weekly topotecan is administered – i.e.i.e., on days 1, 8, and 15 every 4 weeks) or pegylated liposomal doxorubicin or 15 mg/kg once every 3 weeks as an IV infusion in combination with topotecan administered daily for 5 consecutive days every 3 weeks. Avastin® therapy should be discontinued if there are signs of disease progression or unacceptable toxicity.

Dosing regimen in special patient groups

In elderly patients (over 65 years) no dose adjustments are necessary.

The safety and effectiveness of bevacizumab in patients with renal impairment have not been studied.

The safety and effectiveness of bevacizumab in patients with hepatic impairment has not been studied.

The safety and effectiveness of bevacizumab in children and adolescents have not been established.

Instructions for Use, Handling and Disposal

The solution should be inspected for mechanical inclusions and discoloration before use.

The Avastin® product does not contain an antimicrobial preservative, so the prepared solution should be sterile and used immediately. If the drug is not used immediately, the time and conditions of storage of the prepared solution are the responsibility of the user.

The prepared solution may be stored for no more than 24 h at +2° to +8°C if diluted under controlled and validated aseptic conditions.

The chemical and physical stability of the prepared solution (in 0.9% sodium chloride solution) is maintained for 48 h at +2° to +30°C. Unused drug remaining in the bottle shall be destroyed as it contains no preservatives.

Interaction

The effect of antitumor drugs on the pharmacokinetics of Avastin®

There have been no clinically significant effects reported on the pharmacokinetics of Avastin® when used together with chemotherapy. No statistically or clinically significant differences were found in the clearance of Avastin® in patients receiving monotherapy and in patients receiving Avastin® in combination with interferon alfa-2a or other chemotherapeutic agents (IFN, FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/hemcitabine).

The effect of Avastin® on the pharmacokinetics of other antitumor drugs

Avastin® has no significant effect on the pharmacokinetics of irinotecan and its active metabolite (SN38), capecitabine and its metabolites, as well as oxaliplatin (determined by free and total platinum levels), interferon alfa-2a, cisplatin.

There are no reliable data on the effect of Avastin® on the pharmacokinetics of gemcitabine.

The combination of Avastin® and sunitinib The use of Avastin® (10 mg/kg once every 2 weeks) in combination with sunitinib (50 mg daily) in patients with metastatic renal cell cancer has reported cases of microangiopathic hemolytic anemia (MHA). MAHA belongs to a subgroup of hemolytic anemias, which may manifest as erythrocyte fragmentation, anemia and thrombocytopenia. Some patients additionally experience neurological disorders, increased creatinine concentration, arterial hypertension, including hypertensive crisis. These symptoms were reversible after discontinuation of therapy with bevacizumab and sunitinib.

Radiation therapy

The safety profile of Avastin® in combination with radiation therapy and chemotherapy (temozolomide) in patients with newly diagnosed glioblastoma remains unchanged.

The safety and efficacy of Avastin® in combination with radiation therapy for other indications has not been established.

Pharmaceutical interactions

Avastin® is pharmaceutically incompatible with dextrose solutions.

Special Instructions

The patient’s medical records should include the brand name of the drug (Avastin®). Substitutions for any other biologic medication must be approved by your physician. The information in this description only applies to Avastin®.

The treatment with Avastin® must only be given under the care of a physician experienced in antitumor therapy.

In patients treated with Avastin® there is an increased risk of gastrointestinal and gallbladder perforation. Severe cases of gastrointestinal perforation, including fatal, have been observed (in 0.2-1% of all patients treated with Avastin®). The clinical picture of gastrointestinal perforations differed in severity and varied from signs of free gas on abdominal radiography, which disappeared without treatment, to perforations with abdominal abscess and lethal outcome. In some cases, there was initial intraperitoneal inflammation due to gastric ulcer disease, tumor necrosis, diverticulitis, or colitis associated with chemotherapy. The association between the development of intraperitoneal inflammation and gastrointestinal perforation and therapy with Avastin® has not been established. If gastrointestinal perforation occurs, treatment with Avastin® should be discontinued.

Serious cases of fistulas, including death, have been reported with Avastin® therapy. Gastrointestinal fistulas occurred most frequently in patients with metastatic colorectal cancer and ovarian cancer (up to 2% of patients), less frequently in other tumor localizations. Infrequently (≥0.1- < 1%) cases of fistulas of other localizations (bronchopleural, urogenital, biliary) were registered. Fistula formation is more frequently observed within the first 6 months of Avastin® therapy, but can occur both after 1 week and after 1 year or more after initiation of therapy.

Avastin® therapy should be discontinued if a grade 4 tracheo-esophageal fistula or fistula of any localization occurs. There are limited data on the continued use of Avastin® in patients with fistulas of other localizations. Avastin® should be considered for discontinuation in patients with internal fistulas that do not penetrate into the gastrointestinal tract.

In patients receiving Avastin® there is an increased risk of bleeding, especially bleeding from the tumor. Avastin® should be discontinued if bleeding of grade 3 or 4 according to the NCI-CTC classification occurs. Overall incidence of bleeding of grade 3 to 5 during use of Avastin® for all indications is 0.4-6.5%. Bleeding from the tumor or minor bleeding from the mucous membranes and skin (e.g., nasal bleeding) were observed most frequently. Nasal bleeding of 1st degree of severity according to NCI-CTC classification, lasting less than 5 minutes, resolved without medical intervention and did not require changing Avastin® dosing regimen was observed most often. The frequency of minor bleeding from mucous membranes and skin depends on the drug dose. Minor bleeding of the gums or vaginal bleeding occurred less frequently.

Offensive or massive pulmonary bleeding/bleeding has been observed mainly in non-small cell lung cancer. Administration of anti-rheumatic/anti-inflammatory drugs, anticoagulants, prior radiation therapy, atherosclerosis, central location of the tumor, and cavern formation before or during treatment are possible risk factors for pulmonary bleeding/hemoptysis, with only squamous cell lung cancer having a statistically significant association with the development of bleeding.

Patients who have recently had bleeding/hemoptysis (more than 2.5 ml of blood) should not receive Avastin®.

In patients with colorectal cancer, tumor-related GI bleeding, including rectal bleeding and melena, may occur.

Bleeding, including intracranial hemorrhage, has rarely been observed in patients with metastatic CNS lesions or with glioblastoma.

The symptoms of intracranial hemorrhage should be monitored; if so, discontinue therapy with Avastin®.

In patients with congenital hemorrhagic diathesis, acquired coagulopathy, or who received full dose anticoagulants for thromboembolism, caution should be exercised before prescribing Avastin® due to lack of information about safety profile of the drug in these patients. No increase in the incidence of bleeding of grade 3 or higher has been observed in patients treated with Avastin® and warfarin.

An isolated case, as well as a series of cases of serious visual adverse events (including infectious endophthalmitis and other inflammatory diseases) have been reported following unregistered intravitreal administration of Avastin®. Some of these events have resulted in loss of visual acuity of varying severity, including permanent blindness. Avastin® is not indicated for intravitreal administration.

In patients receiving Avastin® there was an increased incidence of arterial hypertension of all degrees of severity (up to 42.1%). For all indications, the incidence of arterial hypertension of NCI-CTC grades 3-4 was 0.4%-17.9%; grade 4 (hypertensive crisis) was observed in 1% of patients.

The clinical safety data suggest that the incidence of BP elevation probably depends on the dose of bevacizumab.

Avastin® should only be administered to patients with previously compensated arterial hypertension with further BP control. There is no information about the effect of Avastin® in patients with uncontrolled arterial hypertension at the time of initiation of therapy. In patients with arterial hypertension requiring drug therapy, it is recommended to temporarily discontinue therapy with Avastin® until normalization of BP is achieved.

In most cases, normalization of BP is achieved with standard antihypertensive agents (ACE inhibitors, diuretics and slow calcium channel blockers) individually selected for each patient. Avastin® therapy was rarely withdrawn or hospitalization was required.

There have been very rare cases of hypertensive encephalopathy, some with a fatal outcome. The risk of arterial hypertension associated with Avastin® therapy did not correlate with patient baseline characteristics, comorbidities, or concomitant therapy.

Avastin® therapy should be discontinued if BP does not normalize or if a hypertensive crisis or hypertensive encephalopathy develops.

Avastin® therapy has reported single cases of posterior reversible encephalopathy syndrome manifested by an epileptic seizure, headache, psychiatric disorders, visual disturbances, lesions of visual cortex centers, with or without arterial hypertension and other symptoms. The diagnosis can be confirmed by brain imaging techniques (preferably MRI). If posterior reversible encephalopathy syndrome develops, symptomatic therapy should be prescribed, BP should be closely monitored and Avastin® should be discontinued. Usually resolution or improvement of symptoms occurs in a few days, but neurological complications have been observed in some patients. The safety of re-administration of Avastin® in such patients has not been established.

The incidence of arterial thromboembolism, including stroke, transient ischemic attack and myocardial infarction and other arterial thromboembolic events was higher with Avastin® therapy in combination with chemotherapy than with chemotherapy alone. The overall incidence of arterial thromboembolism was 3.8%. If arterial thromboembolism occurs, Avastin® therapy should be discontinued. A history of arterial thromboembolism or age over 65 years are associated with an increased risk of arterial thromboembolism during treatment with Avastin®. Caution should be exercised when treating these patients.

Avastin® treatment has an increased risk of venous thromboembolism (TELA, deep vein thrombosis, thrombophlebitis). The overall incidence of venous thromboembolism (deep vein thrombosis and TELA) varies from 2.8% to 17.3%.

Avastin® therapy should be discontinued if there is a life-threatening event (grade 4) of venous thromboembolism, including TELA, and the patient should be monitored closely for venous thromboembolism of ≤3 severity.

Chronic heart failure (CHF) has occurred with Avastin® for all indications, but mainly in metastatic breast cancer. Both asymptomatic decreased left ventricular ejection fraction and CHF that required therapy or hospitalization were observed.

CRC of grade 3 or higher was observed in 3.5% of patients treated with Avastin®. In patients who received Avastin® in combination with anthracyclines, the incidence of CHF of grade 3 or higher did not differ from the available data for therapy of metastatic breast cancer. Most patients had improvement in symptoms and/or left ventricular ejection fraction with appropriate treatment.

There are no data on the risk of CHF development in patients with a history of NYHA class II-IV CHF.

In most cases, CHF occurred in patients with metastatic breast cancer who received anthracycline therapy, had a history of radiation therapy to the chest area, or had other risk factors for CHF.

Avastin® should be used with caution in patients with a history of clinically significant cardiovascular disease, such as coronary heart disease or CHF.

In patients who have not previously received therapy with anthracyclines, the use of Avastin® and anthracyclines did not increase the incidence of CHF of any severity compared to monotherapy with anthracyclines. Grade 3 or higher CHF occurred slightly more frequently in the Avastin® therapy group in combination with chemotherapy compared with chemotherapy alone, which is consistent with other data obtained in patients with metastatic breast cancer who were not receiving concomitant therapy with anthracyclines.

In patients with diffuse B-cell lymphoma, therapy with bevacizumab and doxorubicin at a cumulative dose greater than 300 mg/m² showed an increase in new cases of CHF. When comparing rituximab/cyclophosphamide/doxorubicin/ vincristine/prednisolone (R-CHOP) + bevacizumab and R-CHOP therapy, the number of new cases was not different, but was higher than that previously observed with doxorubicin therapy. The incidence of CHF was higher in the R-CHOP + bevacizumab group.

The drug Avastin® may adversely affect wound healing. Treatment with bevacizumab should be started at least 28 days after major surgery or when the surgical wound is completely healed. If complications related to wound healing develop during treatment, Avastin® should be temporarily withdrawn until the wound is completely healed. Avastin® should also be temporarily discontinued in case of elective surgery.

Rare cases of necrotizing fasciitis (including death) have been reported in patients treated with Avastin®. This complication usually developed against the background of impaired wound healing, gastrointestinal perforation or fistula formation. If necrotizing fasciitis is detected, Avastin® should be withdrawn and appropriate treatment initiated immediately.

Proteinuria was observed in 0.7-38% of patients treated with Avastin®. In terms of severity, proteinuria ranged from transient asymptomatic detection of traces of protein in the urine and in 1.4% of patients to nephrotic syndrome (grade 4 proteinuria). Grade 3 proteinuria was reported in 8.1% of patients treated with Avastin® for various indications. Proteinuria was not associated with impaired renal function and rarely required discontinuation of Avastin® therapy. The risk of proteinuria is increased in patients with a history of arterial hypertension. It is possible that grade 1 proteinuria depends on the dose of Avastin®.

Avastin® should be discontinued if grade 4 proteinuria develops. Urinalysis for proteinuria is recommended before and during therapy with Avastin®.

In most cases of proteinuria ≥2 g/day, therapy with Avastin® has been temporarily suspended until proteinuria decreases < 2 g/day.

Avastin® therapy in combination with myelotoxic chemotherapy regimens has shown an increased incidence of severe neutropenia, febrile neutropenia or infections with severe neutropenia (including fatalities).

Patients may have an increased risk of developing infusion/hypersensitivity reactions. There is evidence of a higher incidence of anaphylactic and anaphylactoid reactions in patients who received Avastin® in combination with chemotherapy compared to patients who received chemotherapy alone.

The careful monitoring of the patient during and after administration of Avastin® is recommended. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical measures taken. Systematic premedication is no guarantee that there will be no infusion/hypersensitivity reactions.

There have been reported cases of osteonecrosis of the jaw in cancer patients receiving Avastin®. Most of these patients had received bisphosphonates by injection previously or as concomitant therapy; osteonecrosis of the jaw is an identified risk for bisphosphonates. Caution should be exercised if Avastin® and bisphosphonates are used concomitantly or sequentially by IV. Invasive dental procedures are also an identified risk factor. Prior to treatment with Avastin® , a dental examination and appropriate preventive dental care should be performed. If possible, invasive dental procedures should be avoided in patients who have previously received or are currently receiving bisphosphonates intravenously.

Patients over 65 years of age: There is an increased risk of arterial thromboembolism (including development of stroke, transient ischemic attack, myocardial infarction), grade 3-4 severe leukopenia and thrombocytopenia, and neutropenia (all severities), diarrhea, nausea, headache and fatigue when Avastin® is prescribed to patients over 65 compared to patients ≤65 years old. No increase of the incidence of other adverse reactions, associated with the use of Avastin® (gastrointestinal perforations, complications related to wound healing, arterial hypertension, proteinuria, CHF and bleeding) was noted in patients older than 65 years old in comparison with patients ≤65 years old.

Disposal of unused or expired medication should be done according to facility requirements.

The effect of the drug on the ability to drive vehicles and other mechanisms requiring increased concentration

There have been no studies of the effect of the drug on the ability to drive vehicles and mechanisms. Patients who have had such adverse events as syncope, somnolence or visual disturbances should abstain from driving vehicles or operating machinery.

Contraindications

• High sensitivity to bevacizumab or any other component of the drug, chinese hamster ovary cell preparations or other recombinant human or near-human antibodies;
• Hepatic and hepatic impairment (efficacy and safety not established).
• renal and hepatic impairment (efficacy and safety of use not established);
• pregnancy;
• breastfeeding period;
• children under 18 years of age (efficacy and safety not established).

With caution: The drug should be administered in a history of arterial thromboembolism; diabetes mellitus; patients over 65 years of age; congenital hemorrhagic diathesis and acquired coagulopathy; taking anticoagulants to treat thromboembolism before starting therapy with Avastin® clinically significant cardiovascular disease (history of CHD or chronic heart failure); arterial hypertension; venous thromboembolism; wound healing; bleeding/hemoptysis; history of gastrointestinal perforation; posterior reversible encephalopathy syndrome; neutropenia; proteinuria.

Side effects

The most serious adverse reactions are gastrointestinal perforations, hemorrhage including pulmonary bleeding/hemoptysis (more common in patients with non-small cell lung cancer), arterial thromboembolism.

In patients treated with Avastin®, the most frequently observed events were: increased BP, weakness or asthenia, diarrhea, and abdominal pain.

The increase in BP and the development of proteinuria are probably dose-dependent.

The following are adverse reactions of all National Cancer Institute (NCI-CTC) classifications of severity seen in patients who received Avastin® in combination with various chemotherapy regimens for all indications.

The following criteria are used to describe the incidence of adverse reactions:

• very frequently (≥10%);
• frequently (≥1%- < 10%);
• infrequent (≥0.1%- < 1%);
• infrequent (≥0.01%- < 0.1%);
• very rare ( < 0.01%).

Unwanted reactions are categorized according to the highest frequency of occurrence. Within a single frequency category, adverse reactions are presented in decreasing order of severity. Some of the listed adverse reactions are frequently seen with chemotherapy (e.g., palmar-toderm syndrome with capecitabine and peripheral sensory neuropathy with paclitaxel or oxaliplatin); however, a worsening of the condition cannot be excluded with Avastin®. Avastin® in combination with pegylated liposomal doxorubicin may increase the risk of palmar plantar syndrome.

Hematopoietic system disorders: very common – febrile neutropenia, leukopenia, neutropenia, thrombocytopenia; common – anemia.

Nervous system disorders: very common – peripheral sensory neuropathy, dysgeusia, headache, dysarthria; common – stroke, syncope, somnolence.

An organ of vision: very common – visual impairment, increased lacrimation.

Cardiovascular system: very common – BP increase; common – chronic heart failure, supraventricular tachycardia, arterial thromboembolism, deep vein thrombosis, bleeding (including pulmonary, intracranial, mucous membrane and skin, GI and tumor).

Respiratory system disorders: very common – dyspnea, nasal bleeding, rhinitis; common – pulmonary embolism (TELA), hypoxia.

Digestive system disorders: very frequently – anorexia, diarrhea, nausea, vomiting, constipation, stomatitis, rectal bleeding; frequently – gastrointestinal perforation, bowel obstruction (including obturation), abdominal pain, gastrointestinal disorders.

Reproductive system disorders: very common – failure of ovarian function (amenorrhea of 3 months or more (FSH concentration ≥30 mEU/ml with negative pregnancy test with determination of human serum beta chorionic gonadotropin)).

Skin and subcutaneous tissue disorders: very common – exfoliative dermatitis, dry skin, changes in skin color; often – palmar-subcutaneous syndrome.

Muscular system: very common – arthralgia; common – muscle weakness, myalgia.

The urinary system: very often – proteinuria; often – urinary tract infection.

Local reactions: very often – pain, including at the site of drug administration.

Others: very common – asthenia, increased fatigue, pyrexia, inflammation of mucous membranes of various localizations; often – lethargy, lethargy, sepsis, abscess, accession of secondary infections, dehydration.

Laboratory measures: hyperglycemia, hypokalemia, hyponatremia, increased prothrombin time, increased MHO.

Postmarketing surveillance

Nervous system disorders: rare – posterior reversible encephalopathy syndrome; very rare – hypertensive encephalopathy.

Cardiovascular system disorders: frequency of occurrence is unknown – thrombotic renal microangiopathy, clinically manifested by proteinuria.

Respiratory system: frequently – dysphonia; frequency of occurrence unknown – nasal septal perforation, pulmonary hypertension.

Gastrointestinal disorders: frequency of occurrence unknown – gastrointestinal ulcer.

Hepatic and biliary tract disorders: frequency of occurrence is unknown – gallbladder perforation.

Allergic and infusion reactions: frequency of occurrence unknown – hypersensitivity reactions, infusion reactions with the following possible simultaneous manifestations: shortness of breath/ difficulty in breathing, hot flashes/ redness/ rash, decreased or increased BP, decreased oxygen saturation, chest pain, chills and nausea/vomiting.

Muscular system: osteonecrosis of the jaw (mainly in patients who received concomitant therapy with bisphosphonates or were previously treated with bisphosphonates).

Others: rare – necrotizing fasciitis, usually against the background of impaired wound healing, gastrointestinal perforation or fistula formation.

Overdose

Symptoms: When bevacizumab is administered at a maximum dose of 20 mg/kg every 2 weeks by IV, severe headache (migraine) has been reported in several patients.

In overdose, these dose-dependent side effects may worsen.

Treatment: there is no specific antidote. Treatment is symptomatic.

Pregnancy use

The drug is contraindicated during pregnancy and while breastfeeding.

Men and women of childbearing age should use reliable contraception during treatment with Avastin® and for at least 6 months after treatment ends.

Avastin® may interfere with fertility in women. In most patients, fertility was restored after discontinuation of Avastin® therapy. Long-term effects of Avastin® therapy on fertility are unknown.

Breastfeeding is not recommended during treatment with Avastin® and for at least 6 months after stopping Avastin® therapy.