Bevacizumab-Nwgd

1 INDICATIONS AND USAGE Jobevne is a vascular endothelial growth factor inhibitor indicated for the treatment of: • Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first-or second-line treatment. ( 1.1 ) • Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen. ( 1.1 ) Limitations of Use : Jobevne is not indicated for adjuvant treatment of colon cancer. ( 1.1 ) • Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment. ( 1.2 ) • Recurrent glioblastoma in adults. ( 1.3 ) • Metastatic renal cell carcinoma in combination with interferon alfa. ( 1.4 ) • Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. ( 1.5 ) • Epithelial ovarian, fallopian tube, or primary peritoneal cancer: o in combination with carboplatin and paclitaxel, followed by Jobevne as a single agent, for stage III or IV disease following initial surgical resection ( 1.6 ) o in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens ( 1.6 ) o in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Jobevne as a single agent, for platinum-sensitive recurrent disease ( 1.6 ) 1.1 Metastatic Colorectal Cancer Jobevne, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or second-line treatment of patients with metastatic colorectal cancer (mCRC). Jobevne, in combination with fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen. Limitations of Use Jobevne is not indicated for adjuvant treatment of colon cancer [see Clinical Studies (14.2) ]. 1.2 First-Line Non-Squamous Non–Small Cell Lung Cancer Jobevne, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC). 1.3 Recurrent Glioblastoma Jobevne is indicated for the treatment of recurrent glioblastoma (GBM) in adults. 1.4 Metastatic Renal Cell Carcinoma Jobevne, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC). 1.5 Persistent, Recurrent, or Metastatic Cervical Cancer Jobevne, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer. 1.6 Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Jobevne, in combination with carboplatin and paclitaxel, followed by Jobevne as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection. Jobevne, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. Jobevne, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Jobevne as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

2 DOSAGE AND ADMINISTRATION Withhold for at least 28 days prior to elective surgery. Do not administer Jobevne 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 Jobevne until at least 28 days following major surgery and until adequate wound healing. 2.2 Metastatic Colorectal Cancer The recommended dosage when Jobevne 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 Jobevne 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 Jobevne 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 Jobevne 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 Jobevne 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 Jobevne Wound Healing Complications [see Warnings and Precautions (5.2) ]. • Any Withhold Jobevne until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established • Necrotizing fasciitis Discontinue Jobevne Hemorrhage [see Warnings and Precautions (5.3) ]. • Grade 3 or 4 Discontinue Jobevne • Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more Withhold Jobevne Thromboembolic Events [see Warnings and Precautions (5.4 , 5.5) ]. • Arterial thromboembolism, severe Discontinue Jobevne • Venous thromboembolism, Grade 4 Discontinue Jobevne Hypertension [see Warnings and Precautions (5.6) ]. • Hypertensive crisis • Hypertensive encephalopathy Discontinue Jobevne • Hypertension, severe (such as Grade 3 and above) Withhold Jobevne until controlled with medical management; resume once controlled Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.7) ]. • Any Discontinue Jobevne Renal Injury and Proteinuria [see Warnings and Precautions (5.8) ]. • Nephrotic syndrome Discontinue Jobevne • Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome Withhold Jobevne until proteinuria less than 2 grams per 24 hours Infusion-Related Reactions [see Warnings and Precautions (5.9) ]. • Severe Discontinue Jobevne • 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 Jobevne 2.9 Preparation and Administration Preparation Use appropriate aseptic technique. Use sterile needle and syringe to prepare Jobevne. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard vial if solution is cloudy, discolored or contains particulate matter. Withdraw necessary amount of Jobevne 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 Jobevne 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 Jobevne 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1) ] . • Surgery and Wound Healing Complications [see Warnings and Precautions (5.2) ]. • Hemorrhage [see Warnings and Precautions (5.3) ]. • Arterial Thromboembolic Events [see Warnings and Precautions (5.4) ]. • Venous Thromboembolic Events [see Warnings and Precautions (5.5) ]. • Hypertension [see Warnings and Precautions (5.6) ]. • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7) ]. • Renal Injury and Proteinuria [see Warnings and Precautions (5.8) ]. • Infusion-Related Reactions [see Warnings and Precautions (5.9) ]. • Ovarian Failure [see Warnings and Precautions (5.11) ]. • Congestive Heart Failure [see Warnings and Precautions (5.12) ]. Most common adverse reactions incidence (incidence > 10%) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), and epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224 AVF4095, GOG-0213, and GOG-0218) or another cancers at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate > 10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14) ]. Metastatic Colorectal Cancer In Combination with bolus-IFL The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), which compared bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus-IFL in patients with mCRC [see Clinical Studies (14.1) ] . Patients were randomized (1:1:1) to placebo with bolus-IFL, bevacizumab with bolus-IFL, or bevacizumab with fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grades 3−4 adverse reactions and selected Grades 1−2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2. Table 2: Grades 3-4 Adverse Reactions Occurring at Higher Incidence (≥ 2%) in Patients Receiving Bevacizumab vs. Placebo in Study AVF2107g Adverse Reaction NCI-CTC version 3. Bevacizumab with IFL (N = 392) Placebo with IFL (N = 396) Hematology Leukopenia 37% 31% Neutropenia 21% 14% Gastrointestinal Diarrhea 34% 25% Abdominal pain 8% 5% Constipation 4% 2% Vascular Hypertension 12% 2% Deep vein thrombosis 9% 5% Intra-abdominal thrombosis 3% 1% Syncope 3% 1% General Asthenia 10% 7% Pain 8% 5% In Combination with FOLFOX4 The safety of bevacizumab was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Selected Grades 3−5 non-hematologic and Grades 4−5 hematologic occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with FOLFOX4 compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse reaction rates due to the reporting mechanisms. First-Line Non-Squamous Non-Small Cell Lung Cancer The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies (14.3) ] . Chemotherapy naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without bevacizumab (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the efficacy population. Only Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions were collected. Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with paclitaxel and carboplatin compared with patients receiving chemotherapy alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thromboembolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Recurrent Glioblastoma The safety of bevacizumab was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of bevacizumab and are considered safety evaluable [see Clinical Studies (14.4) ] . Patients were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. In the bevacizumab with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications. Metastatic Renal Cell Carcinoma The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks) or placebo with interferon alfa [see Clinical Studies (14.5) ] . Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-5 adverse reactions occurring at a higher incidence (> 2%) were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Adverse reactions are presented in Table 3. Table 3: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) of Patients Receiving Bevacizumab vs. Placebo with Interferon Alfa in Study BO17705 Adverse Reaction NCI-CTC version 3. Bevacizumab with Interferon Alfa (N = 337) Placebo with Interferon Alfa (N = 304) Metabolism and nutrition Decreased appetite 36% 31% Weight loss 20% 15% General Fatigue 33% 27% Vascular Hypertension 28% 9% Respiratory, thoracic and mediastinal Epistaxis 27% 4% Dysphonia 5% 0% Nervous system Headache 24% 16% Gastrointestinal Diarrhea 21% 16% Renal and urinary Proteinuria 20% 3% Musculoskeletal and connective tissue Myalgia 19% 14% Back pain 12% 6% The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Cervical Cancer The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.6) ] . Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 218 patients receiving bevacizumab with chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%), proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%), hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%), dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1%). Adverse reactions are presented in Table 4. Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240 Adverse Reaction NCI-CTC version 3. Bevacizumab with Chemotherapy (N = 218) Chemotherapy (N = 222) General Fatigue 80% 75% Peripheral edema 15% 22% Metabolism and nutrition Decreased appetite 34% 26% Hyperglycemia 26% 19% Hypomagnesemia 24% 15% Weight loss 21% 7% Hyponatremia 19% 10% Hypoalbuminemia 16% 11% Vascular Hypertension 29% 6% Thrombosis 10% 3% Infections Urinary tract infection 22% 14% Infection 10% 5% Nervous system Headache 22% 13% Dysarthria 8% 1% Psychiatric Anxiety 17% 10% Respiratory, thoracic and mediastinal Epistaxis 17% 1% Renal and urinary Increased blood creatinine 16% 10% Proteinuria 10% 3% Gastrointestinal Stomatitis 15% 10% Proctalgia 6% 1% Anal fistula 6% 0% Reproductive system and breast Pelvic pain 14% 8% Hematology Neutropenia 12% 6% Lymphopenia 12% 5% Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Stage III or IV Following Initial Surgical Resection The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated the addition of bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection [see Clinical Studies (14.7) ] . Patients were randomized (1:1:1) to carboplatin and paclitaxel without bevacizumab (CPP), carboplatin and paclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent for up to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥2%) in either of the bevacizumab arms versus thecontrol arm were fatigue (CPB15+ -9%, CPB15 -6%, CPP -6%), hypertension (CPB15+ -10%, CPB15 -6%,CPP -2%), thrombocytopenia (CPB15+ -21%, CPB15 -20%, CPP -15%) and leukopenia (CPB15+ -51%,CPB15 -53%, CPP -50%). Adverse reactions are presented in Table 5. Table 5: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in GOG-0218 Adverse Reaction NCI-CTC version 3, Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone CPB15 + , N = (608) Bevacizumab with carboplatin and paclitaxel CPB15, (N = 607) Carboplatin and paclitaxel CPP (N = 602) General Fatigue 80% 72% 73% Gastrointestinal Nausea 58% 53% 51% Diarrhea 38% 40% 34% Stomatitis 25% 19% 14% Musculoskeletal and connective tissue Arthralgia 41% 33% 35% Pain in extremity 25% 19% 17% Muscular weakness 15% 13% 9% Nervous system Headache 34% 26% 21% Dysarthria 12% 10% 2% Vascular Hypertension 32% 24% 14% Respiratory, thoracic and mediastinal Epistaxis 31% 30% 9% Dyspnea 26% 28% 20% Nasal mucosal disorder 10% 7% 4% Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to bevacizumab with chemotherapy or chemotherapy alone in patients with platinum resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within < 6 months from the most recent platinum based therapy [see Clinical Studies (14.8) ] . Patients were randomized to receive bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 179 patients receiving bevacizumab with chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%). Adverse reactions are presented in Table 6. Table 6: Grades 2-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224 Adverse Reaction NCI-CTC version 3. Bevacizumab with Chemotherapy (N = 179) Chemotherapy (N = 181) Hematology Neutropenia 31% 25% Vascular Hypertension 19% 6% Nervous system Peripheral sensory neuropathy 18% 7% General Mucosal inflammation 13% 6% Renal and urinary Proteinuria 12% 0.6% Skin and subcutaneous tissue Palmar-plantar erythrodysaesthesia 11% 5% Infections Infection 11% 4% Respiratory, thoracic and mediastinal Epistaxis 5% 0% Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Study AVF4095g The safety of bevacizumab was evaluated in 247 patients who received at least one dose of bevacizumab in a double-blind study (AVF4095g) in patients with platinum sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer [see Clinical Studies (14.9) ] . Patients were randomized (1:1) to receive bevacizumab (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by bevacizumab or placebo alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with chemotherapy compared to placebo with chemotherapy were: thrombocytopenia (40% vs. 34%), nausea (4% vs. 1.3%), fatigue (6% vs. 4%), headache (4% vs. 0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%), epistaxis (5% vs. 0.4%), and hypertension (17% vs. 0.9%). Adverse reactions are presented in Table 7. Table 7: Grades 1-5 Adverse Reactions Occurring at a Higher Incidence (≥ 5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g Adverse Reaction NCI-CTC version 3 Bevacizumab with Carboplatin and Gemcitabine (N = 247) Placebo with Carboplatin and Gemcitabine (N = 233) General Fatigue 82% 75% Mucosal inflammation 15% 10% Gastrointestinal Nausea 72% 66% Diarrhea 38% 29% Stomatitis 15% 7% Hemorrhoids 8% 3% Gingival bleeding 7% 0% Hematology Thrombocytopenia 58% 51% Respiratory, thoracic and mediastinal Epistaxis 55% 14% Dyspnea 30% 24% Cough 26% 18% Oropharyngeal pain 16% 10% Dysphonia 13% 3% Rhinorrhea 10% 4% Sinus congestion 8% 2% Nervous system Headache 49% 30% Dizziness 23% 17% Vascular Hypertension 42% 9% Musculoskeletal and connective tissue Arthralgia 28% 19% Back pain 21% 13% Psychiatric Insomnia 21% 15% Renal and urinary Proteinuria 20% 3% Injury and procedural Contusion 17% 9% Infections Sinusitis 15% 9% Study GOG-0213 The safety of bevacizumab was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy [see Clinical Studies (14.9) ] . Patients were randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or bevacizumab (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by bevacizumab as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving bevacizumab with chemotherapy compared to chemotherapy alone were: hypertension (11% vs. 0.6%), fatigue (8% vs. 3%), febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%), abdominal pain (6% vs. 0.9%), hyponatremia (4% vs. 0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%). Adverse reactions are presented in Table 8. Table 8: Grades1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213 Adverse Reaction NCI-CTC version 3 Bevacizumab with Carboplatin and Paclitaxel (N = 325) Carboplatin and Paclitaxel (N = 332) Musculoskeletal and connective tissue Arthralgia 45% 30% Myalgia 29% 18% Pain in extremity 25% 14% Back pain 17% 10% Muscular weakness 13% 8% Neck pain 9% 0% Vascular Hypertension 42% 3% Gastrointestinal Diarrhea 39% 32% Abdominal pain 33% 28% Vomiting 33% 25% Stomatitis 33% 16% Nervous System Headache 38% 20% Dysarthria 14% 2% Dizziness 13% 8% Metabolism and nutrition Decreased appetite 35% 25% Hyperglycemia 31% 24% Hypomagnesemia 27% 17% Hyponatremia 17% 6% Weight loss 15% 4% Hypocalcemia 12% 5% Hypoalbuminemia 11% 6% Hyperkalemia 9% 3% Respiratory, thoracic and mediastina l Epistaxis 33% 2% Dyspnea 30% 25% Cough 30% 17% Rhinitis allergic 17% 4% Nasal mucosal disorder 14% 3% Skin and subcutaneous tissue Exfoliative rash 23% 16% Nail disorder 10% 2% Dry skin 7% 2% Renal and urinary Proteinuria 17% 1% Increased blood creatinine 13% 5% Hepatic Increased aspartate aminotransferase 15% 9% General Chest pain 8% 2% Infections Sinusitis 7% 2% 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of bevacizumab or of other bevacizumab products. In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bevacizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General: Polyserositis Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

12.3 Pharmacokinetics The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab once every 2 weeks is 2.8. Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10 th , 90 th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks. Distribution The mean (% coefficient of variation [CV%]) central volume of distribution is 2.9 (22%) L. Elimination The mean (CV%) clearance is 0.23 (33) L/day. The estimated half-life is 20 days (11 to 50 days). Specific Populations The clearance of bevacizumab varied by body weight, sex, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.26 L/day vs. 0.21 L/day) and a larger central volume of distribution (3.2 L vs. 2.7 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.25 L/day vs. 0.20 L/day) than patients with tumor burdens below the median. In Study AVF2107g, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with bevacizumab as compared to females and patients with low tumor burden.