Bevacizumab

28 days prior to elective surgery. Do not administer MVASI for 28 days following major surgery and until adequate wound healing. ( 2.1 ) Metastatic colorectal cancer ( 2.2 ) 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 ( 2.3 ) 15 mg/kg every 3 weeks with carboplatin and paclitaxel Recurrent glioblastoma ( 2.4 ) 10 mg/kg every 2 weeks Metastatic renal cell carcinoma ( 2.5 ) 10 mg/kg every 2 weeks with interferon-alfa Persistent, recurrent, or metastatic cervical cancer ( 2.6 ) 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 ( 2.7 ) 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 ( 2.7 ) 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 ( 2.7 ) 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. See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions ( 2.8 , 2.9 ) 2.1 Important Administration Information Withhold for at least 28 days prior to elective surgery. Do not administer 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. Recurrent Disease Platinum Resistant 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). Platinum Sensitive The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 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 6 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 [see Warnings and Precautions (5.1) ] Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ Discontinue MVASI Wound Healing Complications [see Warnings and Precautions (5.2) ] 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 [see Warnings and Precautions (5.3) ] Grade 3 or 4 Discontinue MVASI Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more Withhold MVASI Thromboembolic Events [see Warnings and Precautions (5.4 , 5.5) ] Arterial thromboembolism, severe Discontinue MVASI Venous thromboembolism, Grade 4 Discontinue MVASI Hypertension [see Warnings and Precautions (5.6) ] Hypertensive crisis Hypertensive encephalopathy Discontinue MVASI Hypertension, severe Withhold MVASI if not controlled with medical management; resume once controlled Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.7) ] Any Discontinue MVASI Renal Injury and Proteinuria [see Warnings and Precautions (5.8) ] 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 [see Warnings and Precautions (5.9) ] 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 [see Warnings and Precautions (5.12) ] 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. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. Discard any unused portion left in a vial, as the product contains no preservatives. Diluted 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. Administration 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.

8.4 Pediatric Use 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 Animal Toxicity Data Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 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.