SIMBIVA

There is a great deal of evidence indicating that vascular endothelial growth factor (VEGF) is important for the survival and proliferation of cancer cells. 14, 6, 8, 24 VEGF plays an important role in angiogenesis, lymphangiogenesis, and tumor growth, which are all factors that contribute to its attractiveness as a therapeutic target for anti-cancer therapies. 5, 7, 6, 8, 9 In 2004, bevacizumab (Avastin) gained FDA approval for specific types of cancer, and became the first antiangiogenic agent introduced to the market. 23, 24 It is a humanized monoclonal IgG antibody, and inhibits angiogenesis by binding and neutralizing VEGF-A. 7, 14 Bevacizumab is generally indicated for use in combination with different chemotherapy regimens which are specific to the type, severity, and stage of cancer.

Bevacizumab was approved by Health Canada on March and by the European Commission on April 21, 2021. 32, 29 There are several biosimilars of bevacizumab, such as bevacizumab-awwb, bevacizumab-maly, bevacizumab-adcd, and bevacizumab-tnjn.

Interestingly, researchers have identified higher VEGF expression in patients with COVID-19, which may contribute to lung pathologies including acute respiratory syndrome (ARDS) and acute lung injury (ALI).

As such, bevacizumab is being investigated for the treatment of lung complications associated with severe cases of COVID-19.

Avzivi® (bevacizumab), a biosimilar of Avastin®, was approved by the EMA in July to treat several types of cancer, including colorectal, breast, lung, kidney, ovarian, and cervical cancer.

As a vascular endothelial growth factor (VEGF) inhibitor, bevacizumab is used in several chemotherapy regimens to treat metastatic colorectal cancer; metastatic, unresectable, locally advanced or recurrent non-squamous non-small cell lung cancer; metastatic renal cell carcinoma; metastatic, persistent, or recurrent cervical cancer; primary peritoneal cancer; epithelial ovarian cancer; fallopian tube cancer; breast cancer; and recurrent glioblastoma. 25, 27, 28, 29, 30, 33 Interestingly, bevacizumab is currently under investigation for the treatment of COVID-19 complications including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).

Bevacizumab binds circulating vascular endothelial-derived growth factor (VEGF) and blocks it from binding to its associated receptors, effectively blunting downstream signaling.

The effects of bevacizumab have been shown to re-establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply, while also improving the delivery of chemotherapeutic drugs to the target area. 14, 18 On the other hand, VEGF signaling is a vital component of several processes including angiogenesis, lymphangiogenesis, blood pressure regulation, wound healing, coagulation, and renal filtration. 5, 7, 19 Although blocking VEGF may inhibit metastatic disease progression, it may also result in unintended effects due to the role of VEGF in several other physiologic processes.

Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. 16, 21, 22 Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered Intravenous, Intramuscular or Subcutaneous. 16, 22 In a single dose (1 mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows 20.

The volume of distribution of bevacizumab is approximately 3.29 L and 2.39 L for the average male and female, respectively.

There are several pathways through which monoclonal antibodies (mAbs) may be cleared.

Non-specific clearance of mAbs refers to target independent pinocytosis, and proteolysis of the protein into small amino acids and peptides in the reticuloendothelial system (RES) and the liver. 15, 16 Target-mediated clearance is a result of specific interactions between the mAb and its target antigen.

Once bound, the antibody-antigen complex may be cleared via lysosomal degradation. 15, 16 Additionally, the production of anti-drug antibodies (ADA), which are a result of an immunogenic response to mAb-based treatment, can form complexes with mAb's and may impact the rate of mAb clearance.

Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions.

Catabolism or excretion are the primary processes of elimination.

The half-life of bevacizumab is estimated to be 20 days (range of 11-50 days). 25, 13.

The clearance (CL) of bevacizumab is approximately 0.207 L/day.

CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or <49 kg respectively.

Males tend to clear bevacizumab at a faster rate than females (26% faster on average).

Other factors including alkaline phosphatase (ALP), serum aspartate aminotransferase (AST), serum albumin, and tumor burden may cause the CL to fluctuate.

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Bevacizumab toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function. 18, 19 Common toxicities associated with bevacizumab include hypertension, gastrointestinal perforation, arterial thromboembolism, reversible posterior leukoencephalopathy syndrome (RPLS), venous thromboembolism, proteinuria, bleeding/hemorrhage, and wound-healing complications.

Withhold for at least 28 days prior to elective surgery.

Do not administer

MVASI for 28 days following major surgery and until adequate wound healing.

Metastatic colorectal cancer 5 mg/kg every 2 weeks with bolus-IFL 10 mg/kg every 2 weeks with FOLFOX4 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line bevacizumab product-containing regimen First-line non-squamous non-small cell lung cancer 15 mg/kg every 3 weeks with carboplatin and paclitaxel Recurrent glioblastoma 10 mg/kg every 2 weeks Metastatic renal cell carcinoma 10 mg/kg every 2 weeks with interferon-alfa Persistent, recurrent, or metastatic cervical cancer 15 mg/kg every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or topotecan given every week 15 mg/kg every 3 weeks with topotecan given every 3 weeks Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles, followed by 15 mg/kg every 3 weeks as a single agent 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles, followed by 15 mg/kg every 3 weeks as a single agent Administer as an intravenous infusion after dilution.

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Information for preparation and administration instructions and dosage modifications for adverse reactions 2.1 Important Administration Information Withhold for at least 28 days prior to elective surgery.

MVASI until at least 28 days following major surgery and until adequate wound healing. 2.2 Metastatic Colorectal Cancer The recommended dosage when MVASI is administered in combination with intravenous fluorouracil-based chemotherapy is: 5 mg/kg intravenously every 2 weeks in combination with bolus-IFL. 10 mg/kg intravenously every 2 weeks in combination with FOLFOX4. 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan.

• or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab product-containing regimen. 2.3 First-Line Non-Squamous Non-Small Cell Lung Cancer The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel. 2.4 Recurrent Glioblastoma The recommended dosage is 10 mg/kg intravenously every 2 weeks. 2.5 Metastatic Renal Cell Carcinoma The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon-alfa. 2.6 Persistent, Recurrent, or Metastatic Cervical Cancer The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin, or in combination with paclitaxel and topotecan. 2.7 Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Stage III or IV Disease Following Initial Surgical Resection The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by MVASI 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week).

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).

The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for to 8 cycles, followed by MVASI 15 mg/kg every 3 weeks as a single agent until disease progression.

The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for to 10 cycles, followed by MVASI 15 mg/kg every 3 weeks as a single agent until disease progression. 2.8 Dosage Modifications for Adverse Reactions Table 1 describes dosage modifications for specific adverse reactions.

No dose reductions for

MVASI are recommended.

Table 1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Gastrointestinal Perforations and Fistulae Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ Discontinue MVASI Wound Healing Complications Any Withhold MVASI until adequate wound healing.

The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established.

Necrotizing fasciitis Discontinue MVASI Hemorrhage

Grade 3 or 4 Discontinue MVASI Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more Withhold MVASI Thromboembolic Events Arterial thromboembolism, severe Discontinue MVASI Venous thromboembolism, Grade 4 Discontinue MVASI Hypertension Hypertensive crisis Hypertensive encephalopathy Discontinue MVASI Hypertension, severe Withhold MVASI if not controlled with medical management; resume once controlled Posterior Reversible Encephalopathy Syndrome (PRES) Any Discontinue MVASI Renal Injury and Proteinuria Nephrotic syndrome Discontinue MVASI Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome Withhold MVASI until proteinuria less than 2 grams per 24 hours Infusion-Related Reactions Severe Discontinue MVASI Clinically significant Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve Mild, clinically insignificant Decrease infusion rate Congestive Heart Failure Any Discontinue MVASI 2.9 Preparation and Administration Preparation Use appropriate aseptic technique.

Use sterile needle and syringe to prepare MVASI.

Visually inspect vial for particulate matter and discoloration prior to preparation for administration.

Discard vial if solution is cloudy, discolored or contains particulate matter.

Withdraw necessary amount of

MVASI and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP.

Discard any unused portion left in a vial, as the product contains no preservatives.

MVASI solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 8 hours, if not used immediately.

No incompatibilities between

MVASI and polyvinylchloride or polyolefin bags have been observed.

Administer as an intravenous infusion.

First infusion

Administer infusion over 90 minutes.

Subsequent infusions

Administer second infusion over 60 minutes if first infusion is tolerated.

Administer all subsequent infusions over 30 minutes if second infusion over 60 minutes is tolerated.

(bevacizumab-awwb) injection is a clear to slightly opalescent, colorless to pale yellow, sterile solution for intravenous infusion supplied as single-dose vials in the following strengths: 100 mg/4 mL (25 mg/mL) (NDC 55513-206-01, 55513-206-21) and 400 mg/16 mL (25 mg/mL) (NDC 55513-207-01, 55513-207-21).

Each carton contains one vial.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light.

Do not freeze or shake the vial or carton.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light.

Do not freeze or shake the vial or carton.

Based on findings from animal studies and their mechanism of action, bevacizumab products may cause fetal harm in pregnant women.

Limited postmarketing reports describe cases of fetal malformations with use of bevacizumab products in pregnancy; however, these reports are insufficient to determine drug associated risks.

In animal reproduction studies, intravenous administration of bevacizumab to pregnant rabbits every 3 days during organogenesis at doses approximately to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects.

Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryofetal development, and postnatal development.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Pregnant rabbits dosed with 10 mg/kg to 100 mg/kg bevacizumab (approximately to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6-18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions.

There were dose-related increases in the number of litters containing fetuses with any type of malformation (42% for the 0 mg/kg dose, 76% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose) or fetal alterations (9% for the 0 mg/kg dose, 15% for the 30 mg/kg dose, and 61% for the 100 mg/kg dose).

Skeletal deformities were observed at all dose levels, with some abnormalities including meningocele observed only at the 100 mg/kg dose level.

Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges.

The safety and effectiveness of bevacizumab products in pediatric patients have not been established.

In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who received bevacizumab.

Bevacizumab products are not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight pediatric patients with relapsed GBM who received bevacizumab and irinotecan.

Addition of bevacizumab to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical studies, one in high grade glioma (n = 121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n = 154).

Based on the population pharmacokinetics analysis of data from 152 pediatric and young adult patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure).

The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

In an exploratory, pooled analysis of 1745 patients from five randomized, controlled studies, 35% of patients were ≥ 65 years old.

The overall incidence of

ATE was increased in all patients receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in patients ≥ 65 years (8% vs. 3%) as compared to patients < 65 years (2% vs. 1%) .