Avastin 400mg bottle 16ml

Trade name

Avastin

International non-proprietary name

Bevacizumab

Dosage Form

Concentrate for solution for infusion

Composition

1 bottle contains:

active substance: Bevacizumab - 100 mg (concentration in the vial is 100 mg / 4 ml) / 400 mg (concentration in the vial is 400 mg / 16 ml);

Excipients: α, α-trehalose dihydrate - 240.0 / 960.0 mg, sodium dihydrogen phosphate monohydrate - 23.2 / 92.8 mg, sodium anhydrous hydrogen phosphate - 4.8 / 19.2 mg, polysorbate 20 - 1.6 / 6.4 mg, water for injection up to 4.0 / 16.0 ml.

Description

Transparent or opalescent, colorless or slightly brownish liquid.

Pharmacotherapeutic group

Antitumor agent, monoclonal antibodies.

pharmachologic effect

Pharmacodynamics

Drug Avastin ^® (bevacizumab) is a humanized recombinant hyperchimeric monoclonal antibody that binds selectively to a biologically active vascular endothelial growth factor (VEGF) and neutralizes it. Drug Avastin^® inhibits the binding of vascular endothelial growth factor with its type 1 and type 2 receptors (Flt-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 mouse hyperchimeric antibody that binds to VEGF.Bevacizumab is produced by recombinant deoxyribonucleic acid (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 introduction of bevacizumab results in the suppression of the metastatic progression of the disease and the reduction of microvascular permeability in various human tumors, including cancer of the colon, mammary gland, pancreas and prostate gland.

Preclinical safety data

The carcinogenic and mutagenic potential of Avastin^® not studied

With the introduction of the animal drug Avastin^® embryotoxic and teratogenic effects were observed.

In actively growing animals with open growth zones, the use of the drug Avastin^®associated with cartilage dysplasia.

Pharmacokinetics

The pharmacokinetics of the drug Avastin was studied.^® after intravenous administration (iv) in various doses (0.1-10 mg / kg every week; 3-20 mg / kg every 2 or 3 weeks; 5 mg / kg every 2 weeks or 15 mg / kg every 3 weeks) patients with various solid tumors.

The pharmacokinetics of bevacizumab, as well as other antibodies, is described by a two-chamber model. Distribution of the drug Avastin^® characterized by low ground clearance, low volume distribution in the central chamber (V_with) and a long half-life, which helps to maintain the required therapeutic plasma concentration of the drug with the introduction of 1 every 2-3 weeks.

The clearance of bevacizumab does not depend on the age of the patient.

According to population pharmacokinetic meta-analysis, there were no significant differences in bevacizumab pharmacokinetics depending on race when included in body weight analysis or depending on age (there was no correlation between creatinine clearance and age of the patient [median of age - 59 years, and 5th and 95 percentiles - 37 and 76 years]).

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

Distribution

V_with is 2.73 L and 3.28 L in women and men, respectively, which corresponds to the volume of distribution of class G immunoglobulins (IgG) and other monoclonal antibodies. Volume of distribution in the peripheral chamber (V_R) is 1.69 l and 2.35 l in women and men, respectively, in the appointment of bevacizumab with other anticancer drugs. After dose adjustment taking into account body weight in men V_with20% more than women.

Metabolism

After a single IV¹²⁵I-bevacizumab its metabolic characteristics are similar to those of the natural IgG molecule, which does not bind to VEGF. The metabolism and elimination of bevacizumab corresponds to the metabolism and elimination of endogenous IgG, i.e. mainly carried out by proteolytic catabolism in all cells of the body, including endothelial cells, and not through the kidneys and liver. The binding of IgG to neonatal receptors on the crystallizing IgG fragment (FcRn receptors) protects it from cellular metabolism and provides a long half-life.

Removal

The pharmacokinetics of bevacizumab in the dose range from 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 dose adjustment taking into account body weight in men, bevacizumab clearance 17% more than women. According to the two-chamber model, the half-life for women is 18 days, and for men - 20 days.

Pharmacokinetics in Special Patient Groups

Elderly patients (over 65)

There were no significant differences in bevacizumab pharmacokinetics depending on age.

Kids and teens

Bevacizumab pharmacokinetics were evaluated in patients in clinical studies using a population-based pharmacokinetic model (patient age: 7 months – 21 years; body weight: 5.9 - 125 kg). The results of the study of pharmacokinetics showed that the clearance and distribution of bevacizumab were comparable in pediatric patients and adult patients with a normalized body weight. Age did not affect the values ​​of bevacizumab pharmacokinetics when adjusted for body weight.

Patients with renal failure

The safety and effectiveness of bevacizumab in patients with renal insufficiency has not been studied, because The kidneys are not the main organs of metabolism and elimination of bevacizumab.

Patients with liver failure

The safety and efficacy of bevacizumab in patients with hepatic insufficiency has not been studied, becausethe liver is not the main organ of metabolism and elimination of bevacizumab.

Indications

Metastatic colorectal cancer:

• in combination with fluoropyrimidine derivative Chemotherapy.

Locally recurrent or metastatic breast cancer:

• as first-line therapy in combination with Paclitaxel.

Common inoperable, metastatic or recurrent non-cellular lung cancer:

• as a first-line treatment in addition to platinum-based chemotherapy;
• as a first-line treatment for widespread inoperable, metastatic or recurrent non-small cell non-small cell lung cancer with activating mutations in the EGFR gene (epidermal growth factor receptor) in combination with erlotinib.

Common and / or metastatic renal cell carcinoma:

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

Glioblastoma (glioma of the IV degree of malignancy according to the classification of the World Health Organization (WHO)):

• in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma;
• in monotherapy or in combination with irinotecan for the recurrence of glioblastoma or disease progression.

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

• as a first-line therapy in combination with carboplatin and paclitaxel for common (IIIB, IIIC and IV stages according to the classification of the International Federation of Obstetricians-Gynecologists (FIGO)) epithelial cancer of the ovary, fallopian tube and primary peritoneal cancer
• in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel in relapsed, platinum-sensitive epithelial cancer of the ovary, fallopian tube and primary peritoneal cancer in patients who have not previously received bevacizumab or other VEGF inhibitors;
• in combination with paclitaxel, or topotecan, or pegylated liposomal doxorubicin in relapsed, platinum-resistant epithelial cancer of the ovary, fallopian tube, and primary peritoneal cancer in patients who have previously received no more than two chemotherapy regimens.

Persistent, recurrent or metastatic cervical cancer:

• in combination with paclitaxel and Cisplatin or paclitaxel and topotecan.

Contraindications

Hypersensitivity to bevacizumab or to any other component of the preparation, preparations based on Chinese hamster ovary cells or to other recombinant human or close to human antibodies.

Pregnancy and lactation period.

Children under 18 years old, renal and hepatic failure (efficacy and safety of use have not been established).

Carefully

With arterial thromboembolism in history; diabetes; age over 65; congenital hemorrhagic diathesis and acquired coagulopathy; when taking anticoagulants for the treatment of thromboembolism before starting treatment with Avastin^®; a clinically significant cardiovascular disease (ischemic heart disease or a history of chronic heart failure); hypertension; venous thromboembolism; wound healing; bleeding / hemoptysis; a history of gastrointestinal perforation; posterior reversible encephalopathy syndrome; neutropenia; proteinuria.

Dosage and administration

Drug Avastin^® administered only intravenously; it is impossible to inject the drug intravenously with a bolus or bolus!

Drug Avastin^® not intended for intravitreal administration.

Drug Avastin^® pharmaceutically incompatible with dextrose solutions.

The required amount of the drug Avastin^® diluted to the required volume with 0.9% sodium chloride solution in compliance with the rules of asepsis. The concentration of bevacizumab in the prepared solution should be in the range of 1.4-16.5 mg / ml.

Starting dose the drug is administered over 90 minutes as an intravenous 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 performed within 30 minutes.

It is not recommended to reduce the dose of bevacizumab due to adverse events. If necessary, treatment with Avastin^® should be completely or temporarily discontinued.

Standard dosing regimen

Metastatic colorectal cancer

As a first line therapy: 5 mg / kg once every 2 weeks or 7.5 mg / kg once every 3 weeks as an intravenous infusion for a long time.

It is recommended to carry out therapy with Avastin^® until signs of disease progression or unacceptable toxicity appear.

As a second-line therapy: patients previously treated with Avastin^®, after the first progression of the disease can continue treatment with Avastin^® subject to change in chemotherapy regimen:

- with the progression of the disease after first-line therapy, which included the drug Avastin^®: 5 mg / kg once every 2 weeks or 7.5 mg / kg once every 3 weeks as an intravenous infusion for a long time;

- with the progression of the disease after first-line therapy, not including the drug Avastin^®: 10 mg / kg once every 2 weeks or 15 mg / kg once every 3 weeks as an intravenous infusion for a long time.

Locally recurrent or metastatic breast cancer (BC)

10 mg / kg once every 2 weeks as an intravenous infusion for a long time.

If there is evidence of disease progression or unacceptable toxicity, Avastin therapy^® should stop.

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