Avastin, 100 mg/4 ml

Pharmacological action Pharmacological action is antitumor.

Pharmacodynamics

The mechanism of action

The mechanism of action of paclitaxel is based on its ability to stimulate the assembly of microtubules of the mitotic spindle from dimeric tubulin molecules and stabilize microtubules by inhibiting their depolymerization. This leads to the suppression of the normal dynamic reorganization of the microtubule network in the interphase of mitosis and also causes the formation of abnormal clusters of microtubules throughout the cell cycle and the appearance of multiple star-shaped clusters (asters) in the mitosis phase.

Abraxan contains nanodispersed paclitaxel stabilized by albumin with nanoparticle size of approximately 130 nm with paclitaxel in a non-crystalline (amorphous) state.

After injection the nanoparticles rapidly dissociate to form soluble paclitaxel complexes bound to albumin with an approximate size of 10 nm. Albumin is known to regulate the transendothelial transport of plasma components, and in in vitro studies it was demonstrated that the presence of albumin in Abraxane stimulates paclitaxel transport through the endothelial cell layer. It has been hypothesized that transendothelial transport is mediated by the albumin transporter gp-60 and there is increased cumulation of paclitaxel in the tumor due to the presence of an albumin-binding protein, acid secreted cysteine-rich protein (SPARC).

Pharmacokinetics

The pharmacokinetics (PK) of paclitaxel have been studied in clinical studies at 30- and 180-minute infusions of Abraxane at doses ranging from 80 to 375 mg/m2. AUC values for paclitaxel increased linearly, from 2653 to 16736 ng/h/mL over a dose range of 80 to 300 mg/m2.

In a study involving patients with advanced solid tumors, paclitaxel parameters (FC) after an IV injection of Abraxane at a dose of 260 mg/m2 for 30 minutes were compared with FC parameters after administration of solvent-based paclitaxel at a dose of 175 mg/m2 for 3 hours. Based on the uncompartmentalized analysis, paclitaxel clearance (43%) and its Vd (53%) were higher with administration of Abraxane than with solvent-based paclitaxel.

No differences in terminal T1/2 were reported. In a study of multiple IV infusions of Abraxane at a dose of 260 mg/m2 in 12 patients, intraindividual variability in paclitaxel systemic exposure (AUC) was 19% (range of values = 3.21-27.7%). No evidence of paclitaxel cumulation was recorded with multiple courses of therapy.

Distribution. After administration of Abraxane to patients with solid tumors, paclitaxel was evenly distributed in blood cells, plasma and 94% bound to plasma proteins. Binding of paclitaxel to proteins was assessed by ultrafiltration in a comparison study in the same patient. The fraction of free paclitaxel was significantly higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%). This provided significantly higher exposure values of the unbound fraction of paclitaxel when administered with Abraxane than with solvent-based paclitaxel, even with comparable values of total exposure.

This phenomenon is probably due to the lack of paclitaxel binding to Cremophor EL micelles that is observed with solvent-based paclitaxel. According to published studies that evaluated in vitro binding of paclitaxel (at concentrations from 0.1 to 50 µg/ml) to human plasma proteins, the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine had no effect on paclitaxel binding to plasma proteins.

In view of the results of a population-based analysis of FC data, the total Vd is approximately 1741 L; a large Vd indicates intense extravascular distribution and/or binding of paclitaxel to tissue proteins.

Metabolism and excretion. In in vitro studies using liver microsomes and human tissue slices have shown that paclitaxel is metabolized predominantly to form 6α-hydroxypaclitaxel and two additional metabolites present in smaller amounts (3′-n-hydroxypaclitaxel and 6α-3′-n-dihydroxypaclitaxel). The formation of these hydroxylated metabolites is catalyzed by cytochrome P450 system isoenzymes CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4, respectively.

In patients with metastatic breast cancer, after an IV drip injection of Abraxane for 30 minutes at a dose of 260 mg/m2, the mean cumulative urinary excretion of unchanged active ingredient corresponded to 4% of the total drug dose administered; less than 1% of the administered dose were the urinary excreted metabolites 6α-hydroxypaclitaxel and 3′-n-hydroxypaclitaxel, indicating significant extrarenal clearance of the drug. Paclitaxel is predominantly eliminated by hepatic metabolism and excretion with bile. When administered at a therapeutic dose of 80 to 300 mg/m2, mean plasma clearance of paclitaxel ranges from 13 to 30 L/h/m2, and mean terminal T1/2 ranges from 13 to 27 h.

Particular patient groups

Hepatic impairment. The results of the clinical studies demonstrated that mild hepatic insufficiency (total bilirubin >1 to ≤1.5×VGN) had no clinically significant effect on the FC parameters of paclitaxel. In patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3×VGN) and severe (total bilirubin >3 to ≤5×VGN), a 22-26% decrease in the maximum elimination rate of paclitaxel and an approximately 20% increase in the mean AUC of paclitaxel were observed.

Hepatic insufficiency had no effect on the mean Cmax value of paclitaxel. In addition, paclitaxel elimination was inversely correlated with measures of total bilirubin and directly correlated with measures of plasma albumin concentration.

Pharmacokinetic/pharmacodynamic modeling showed no correlation between liver function (as measured by baseline albumin or total bilirubin concentration) and neutropenia in relation to Abraxane exposure. FC analysis was not performed in patients with total bilirubin >5×VGN or patients with metastatic pancreatic adenocarcinoma (see “Dosage and administration”).

Kidney function impairment. Mild to moderate renal impairment (creatinine Cl ≥30 to <90 ml/min) had no clinically significant effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel. There is insufficient FC analysis data for patients with severe renal impairment and no data for patients with end-stage renal failure.

Elderly patients. A population-based FC analysis of Abraxane included data from patients aged 24 to 85 years. The results showed that age had no significant effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

Pharmacokinetic/pharmacodynamic modeling using data from 125 patients with advanced solid tumors showed that patients aged >65 years may be more prone to develop neutropenia during the first cycle of therapy, although age had no effect on plasma paclitaxel exposure.

Other intrinsic factors. A population-based FC analysis of Abraxane demonstrated that gender, race (mongoloid vs. Caucasoid) and type of sólid tumors had no clinically significant effect on the systemic exposure (AUC and Cmax) of paclitaxel. The AUC of paclitaxel in patients with a body weight of 50 kg is approximately 25% lower than in patients with a body weight of 75 kg. The clinical significance of these data is unknown.

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 100 mg.

Associates:

α,α-trehalose dihydrate – 240 mg,

sodium dihydrophosphate monohydrate – 23.2 mg,

p> sodium hydrophosphate anhydrous – 4.8 mg,

Polysorbate 20 – 1.6 mg,

d/i water – up to 4 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/gemcitabine).

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).

MAH belongs to a subgroup of hemolytic anemias, which may manifest as erythrocyte fragmentation, anemia and thrombocytopenia. Some patients additionally experience neurological abnormalities, 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 varied in severity and ranged 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 as a result of peptic 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, lesion 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 closely monitored 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, an increase in new cases of CHF was observed with therapy with bevacizumab and doxorubicin at a cumulative dose greater than 300 mg/m2. 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 high 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: incidence unknown – hypersensitivity reactions, infusion reactions with the following possible simultaneous manifestations: shortness of breath/ difficulty in breathing, flushes/ 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 case of overdose, the listed 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.