Bevacimab IV Infusion 100 mg/4 ml

Uses

Bevacimab IV Infusion 100 mg/4 ml is a vascular endothelial growth factor-specific angiogenesis inhibitor used for the treatment of

• Metastatic colorectal cancer, with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment

• Metastatic colorectal cancer, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Bevacimab IV Infusion 100 mg/4 ml containing regimen

• Non-squamous non-small cell lung cancer, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.• Glioblastoma, as a single agent for adult patients with progressive disease following prior therapy

• Effectiveness based on improvement in objective response rate. No data available demonstrating improvement in disease-related symptoms or survival with Bevacimab IV Infusion 100 mg/4 ml.

• Metastatic renal cell carcinoma with interferon alfa Cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease

• Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan

Limitation of Use: Bevacimab IV Infusion 100 mg/4 ml is not used for adjuvant treatment of colon cancer.

Bevacimab IV Infusion 100 mg/4 ml is also used to associated treatment for these conditions: Cervical Cancer Metastatic, Metastatic Colorectal Cancer (MCRC), Metastatic Non-Squamous Non-Small Cell Lung Cancer, Metastatic Renal Cell Carcinoma, Persistent Cervical Cancer, Recurrent Cervical Cancer, Recurrent Glioblastoma, Stage III epithelial ovarian cancer following initial surgical resection, Stage IV epithelial ovarian cancer following initial surgical resection, Fallopian tube cancer following initial surgical resection, Locally advanced nonsquamous non-small cell lung cancer, Primary peritoneal cancer following initial surgical resection, Recurrent Non-Squamous Non-Small Cell Lung Cancer, Recurrent Platinum-Sensitive Epithelial Ovarian Cancer, Recurrent Platinum-resistant Epithelial Ovarian Cancer, Recurrent platinum drug resistant Fallopian tube cancer, Recurrent platinum drug resistant primary peritoneal cancer, Recurrent platinum sensitive primary peritoneal cancer, Recurrent platinum-sensitive fallopian tube cancer, Unresectable Non-Squamous Non-Small-Cell Lung Cancer

How Bevacimab IV Infusion 100 mg/4 ml works

Transcription of the VEGF protein is induced by 'hypoxia inducible factor' (HIF) in a hypoxic environment. When circulating VEGF binds to VEGF receptors (VEGFR-1 and VEGFR-2) located on endothelial cells, various downstream effects are initiated. It should be noted that VEGF also binds to the neuropilin co-receptors (NRP-1 and NRP-1), leading to enhanced signaling.

Cancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network. The hypoxic microenvironment promoted by cancer cells favors the survival of more aggressive tumor cells, and gives rise to a challenging environment for immune cells to respond appropriately. As a result, VEGF has become a well-known target for anti-cancer drugs like bevacizumab. Bevacimab IV Infusion 100 mg/4 ml is a mAb that exerts its effects by binding and inactivating serum VEGF. When bound to the mAb, VEGF is unable to interact with its cell surface receptors, and proangiogenic signalling is inhibited. This prevents formation of new blood vessels, decreases tumor vasculature, and reduces tumor blood supply.

There is also evidence to suggest that VEGF is upregulated in COVID-19 patients, hence, bevacizumab is being investigated for the treatment of associated complications. Higher levels of VEGF may contribute to pulmonary edema, leading to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Researchers are hopeful that by inhibiting VEGF, bevacizumab may effectively treat ARDS and ALI - both common features of severe COVID-19 cases.

Dosage

Bevacimab IV Infusion 100 mg/4 ml dosage

Bevacimab IV Infusion 100 mg/4 ml should not be administered as an IV push or bolusBevacimab IV Infusion 100 mg/4 ml should not be initiated for 28 days following major surgery and until surgical wound is fully healed

• Metastatic colorectal cancer5 mg/kg IV every 2 weeks with bolus-IFL10 mg/kg IV every 2 weeks with FOLFOX45 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line Bevacimab IV Infusion 100 mg/4 ml containing regimen

• Non-squamous non-small cell lung cancer15 mg/kg IV every 3 weeks with carboplatin/paclitaxel• Glioblastoma10 mg/kg IV every 2 weeks

• Metastatic renal cell carcinoma (mRCC)10 mg/kg IV every 2 weeks with interferon alfa

• Persistent, recurrent, or metastatic carcinoma of the cervix15 mg/kg IV every 3 weeks with paclitaxel/cisplatin or paclitaxel/topotecan

• Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin or weekly topotecan 15 mg/kg IV every 3 weeks with topotecan given every 3 weeks

Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion. Do not initiate Bevacimab IV Infusion 100 mg/4 ml until at least 28 days following major surgery. Administer Bevacimab IV Infusion 100 mg/4 ml after the surgical incision has fully healed.

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 infusion over 60 minutes is tolerated.

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Bevacimab IV Infusion 100 mg/4 ml 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.

Side Effects

Most common adverse reactions incidence (> 10% and at least twice the control arm rate) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Some of the adverse reactions are commonly seen with chemotherapy; however, Bevacimab IV Infusion 100 mg/4 ml may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel.

Toxicity

Bevacimab IV Infusion 100 mg/4 ml toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function. 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.

Precaution

Perforation or Fistula: Bevacimab IV Infusion 100 mg/4 ml should be discontinued if perforation or fistula occurs.

Arterial Thromboembolic Events (e.g., myocardial infarction, cerebral infarction): Bevacimab IV Infusion 100 mg/4 ml should be discontinued for severe ATE.

Venous Thromboembolic Events: Bevacimab IV Infusion 100 mg/4 ml should be discontinued for life-threatening VTEHypertension: Monitor blood pressure and treat hypertension. Temporarily suspend Avastin if not medically controlled. Bevacimab IV Infusion 100 mg/4 ml should be discontinued for hypertensive crisis or hypertensive encephalopathy

Posterior Reversible Encephalopathy Syndrome (PRES): Bevacimab IV Infusion 100 mg/4 ml should be discontinuedProteinuria: Urine protein should be monitored. Bevacimab IV Infusion 100 mg/4 ml should be discontinued for nephrotic syndrome. Bevacimab IV Infusion 100 mg/4 ml should be temporarily discontinued for moderate proteinuria.

Infusion Reactions: Bevacimab IV Infusion 100 mg/4 ml should be stopped in case of severe infusion reactions.

Embryo-fetal Toxicity: Females should be advised of the potential risk to a fetus and the need for use of effective contraception

Ovarian Failure: Females should be advised of the potential risk

Interaction

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Bevacimab IV Infusion 100 mg/4 ml. The results demonstrated no significant effect of Bevacimab IV Infusion 100 mg/4 ml on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Bevacimab IV Infusion 100 mg/4 ml. However, 3 of the 8 patients receiving Bevacimab IV Infusion 100 mg/4 ml plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Bevacimab IV Infusion 100 mg/4 ml had a greater paclitaxel exposure at Day 63 than at Day 0.

Food Interaction

Bevacimab IV Infusion 100 mg/4 ml Drug Interaction

Unknown: arginine, arginine, levocarnitine, levocarnitine, cysteine, cysteine, lithium, lithium, valproic acid, valproic acid, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, phytonadione, phytonadione, menaquinone, menaquinone

Bevacimab IV Infusion 100 mg/4 ml Disease Interaction

Major: fistula formation, GI perforationModerate: bleeding, hypertension, PRES, proteinuria, thromboembolic disorders

Volume of Distribution

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

Elimination Route

Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously.

In a single dose (1mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows: Geometric mean Cmax = 17.38 ug/mL Geometric mean AUCinf = 5,358 ugxh/mL Geometric mean Tmax = 2.50 hrs

Half Life

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

Clearance

The clearance (CL) of bevacizumab is approximately 0.207 L/day. The CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or 14 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.

Elimination Route

Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions. Catabolism or excretion are the primary processes of elimination.

Pregnancy & Breastfeeding use

Bevacimab IV Infusion 100 mg/4 ml may cause fetal harm based on findings from animal studies and the drug’s mechanism of action. Pregnant women should be advised of the potential risk to a fetus.

No data are available regarding the presence of Bevacimab IV Infusion 100 mg/4 ml in human milk, the effects on the breast fed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Bevacimab IV Infusion 100 mg/4 ml, nursing woman should be advised that breastfeeding is not recommended during treatment with Bevacimab IV Infusion 100 mg/4 ml.

Pediatric UseSafety and effectiveness of Bevacimab IV Infusion 100 mg/4 ml have not been established in pediatric patients.

Contraindication

There are no contraindications listed in the manufacturer’s labeling.

Special Warning

The safety, effectiveness and pharmacokinetic profile of Bevacimab IV Infusion 100 mg/4 ml 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 have received Bevacimab IV Infusion 100 mg/4 ml. Bevacimab IV Infusion 100 mg/4 ml is not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with Bevacimab IV Infusion 100 mg/4 ml and irinotecan. There is insufficient information to determine the safety and efficacy of Bevacimab IV Infusion 100 mg/4 ml in children with glioblastoma.

Acute Overdose

The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Interaction with other Medicine

A drug interaction study was performed in which Irinotecan was administered as part of the FOLFIRI regimen with or without Bevacimab IV Infusion 100 mg/4 ml. The results demonstrated no significant effect of Bevacimab IV Infusion 100 mg/4 ml on the pharmacokinetics of Irinotecan or its active metabolite SN38.

Storage Condition

Bevacimab IV Infusion 100 mg/4 ml vials are stable at 2 to 8° C. Bevacimab IV Infusion 100 mg/4 ml vials should be protected from light. Do not freeze or shake. Diluted Bevacimab IV Infusion 100 mg/4 ml solutions may be stored at 2 to 8° C for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Bevacimab IV Infusion 100 mg/4 ml and polyvinylchloride or polyolefin bags have been observed.

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