Avzivi

1 INDICATIONS AND USAGE Avzivi is a vascular endothelial growth factor inhibitor indicated for the treatment of: Metastatic colorectal cancer, in combination with intravenous fluorouracil­based 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 : Avzivi 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 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 ) 1.1 Metastatic Colorectal Cancer Avzivi, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or second-line treatment of patients with metastatic colorectal cancer (mCRC). Avzivi, 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 : Avzivi 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 Avzivi, 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 Avzivi is indicated for the treatment of recurrent glioblastoma (GBM) in adults. 1.4 Metastatic Renal Cell Carcinoma Avzivi, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC). 1.5 Persistent, Recurrent, or Metastatic Cervical Cancer Avzivi, 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 Avzivi, 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.

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 Bio-Thera Solutions, Ltd. at 400-999-8703 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), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224), or other 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 R e action a Bevacizumab with IFL ( N=392) P lacebo with IFL ( N=396) Hematology Leukopenia 37% 31% Neutropenia 21% 14% G astrointestinal 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% a NCI-CTC version 3 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 a 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% a NCI-CTC version 3 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 a 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% a NCI-CTC version 3 Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer 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 5. Table 5: Grades 2−4 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224 Adverse Reaction a 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% a NCI-CTC version 3 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 C ardiovascular: Pulmonary hypertension, Mesenteric venous occlusion Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation M usculoskeletal 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

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Bevacizumab-tnjn is a vascular endothelial growth factor inhibitor. Bevacizumab-tnjn is a recombinant humanized monoclonal IgG1 antibody that contains human framework regions and murine complementarity-determining regions. Bevacizumab-tnjn has an approximate molecular weight of 149 kDa. Bevacizumab-tnjn is produced in a mammalian cell (Chinese Hamster Ovary) expression system. Avzivi (bevacizumab-tnjn) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in a single-dose vial for intravenous use. Avzivi contains bevacizumab-tnjn at a concentration of 25 mg/mL in either a 100 mg/4 mL or 400 mg/16 mL single-dose vial. Each mL of solution contains 25 mg bevacizumab-tnjn, dibasic sodium phosphate (1.2 mg), monobasic sodium phosphate (5 mg), polysorbate 20 (0.4 mg), trehalose (54.3 mg) , and Water for Injection, USP. The pH is 6.1.

2 DOSAGE AND ADMINISTRATION Withhold for at least 28 days prior to elective surgery. Do not administer Avzivi 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 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 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 Avzivi until at least 28 days following major surgery and until adequate wound healing. 2.2 Metastatic Colorectal Cancer The recommended dosage when Avzivi 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 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). 2.8 Dosage Modifications for Adverse Reactions Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for Avzivi are recommended. T able 1: Dosage Modifications for Adverse Reactions A dverse Reaction Severity D osage 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 Avzivi Wound Healing Complications [see Warnings and Precautions ( 5.2 )]. Any Withhold Avzivi until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complications has not been established. Necrotizing fasciitis Discontinue Avzivi Hemorrhage [see Warnings and Precautions ( 5.3 )]. Grade 3 or 4 Discontinue Avzivi Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more Withhold Avzivi Thromboembolic Events [see Warnings and Precautions ( 5.4 , 5.5 )]. Arterial thromboembolism, severe Discontinue Avzivi Venous thromboembolism, Grade 4 Discontinue Avzivi Hypertension [see Warnings and Precautions ( 5.6 )]. Hypertensive crisis Hypertensive encephalopathy Discontinue Avzivi Hypertension, severe Withhold Avzivi if not controlled with medical management; resume once controlled Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.7 )]. Any Discontinue Avzivi Renal Injury and Proteinuria [see Warnings and Precautions ( 5.8 )]. Nephrotic syndrome Discontinue Avzivi Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome Withhold Avzivi until proteinuria less than 2 grams per 24 hours Infusion-Related Reactions [see Warnings and Precautions ( 5.9 )]. Severe Discontinue Avzivi 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 Avzivi 2.9 Preparation and Administration Preparation Use appropriate aseptic technique. Use sterile needle and syringe to prepare Avzivi. 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 Avzivi 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 Avzivi 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 Avzivi 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.

7 DRUG INTERACTIONS Effects of Avzivi on Other Drugs No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon alfa, carboplatin or paclitaxel was observed when bevacizumab was administered in combination with these drugs; however, 3 of the 8 patients receiving bevacizumab with paclitaxel and carboplatin had lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel and carboplatin alone had a greater paclitaxel exposure at Day 63 than at Day 0.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. 12.2 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 (10th, 90th 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.

20241009

3

3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to slightly opalescent, colorless to pale brown solution in a single-dose vial. Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) in a single-dose vial. ( 3 )

Avzivi tnjn bevacizumab TREHALOSE DIHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE POLYSORBATE 20 WATER BEVACIZUMAB-TNJN BEVACIZUMAB-TNJN Avzivi bevacizumab-tnjn TREHALOSE DIHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE POLYSORBATE 20 WATER BEVACIZUMAB-TNJN BEVACIZUMAB-TNJN

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to assess potential of bevacizumab products for carcinogenicity or mutagenicity. Bevacizumab products may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident. 13.2 Animal Toxicology and/or Pharmacology Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

BLA761198

Avzivi

bevacizumab-tnjn

82143-002

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 4 mL Vial Carton NDC 82143-001-01 Avzivi ® (bevacizumab-tnjn) Injection 100 mg/4 mL (25 mg/mL) For Intravenous Use. Single-Dose Vial. Discard Unused Portion. Recommended Dosage: See Prescribing Information. Refrigerate at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Rx only Bio-Thera Solutions, Ltd. US Licence No.: XXXX 100 mg carton

17 PATIENT COUNSELING INFORMATION Gastrointestinal Perforations and Fistulae : bevacizumab products may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [ see Warnings and Precautions ( 5.1 )]. S urgery and Wound Healing Complications : bevacizumab products can increase the risk of wound healing complications. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions ( 5.2 )] . Hemorrhage : bevacizumab products can increase the risk of hemorrhage. Advise patients to immediately contact their health care provider for signs and symptoms of serious or unusual bleeding including coughing or spitting blood [see Warnings and Precautions ( 5.3 )] . Arterial and Venous Thromboembolic Events : bevacizumab products increase the risk of arterial and venous thromboembolic events. Advise patients to immediately contact their health care provider for signs and symptoms of arterial or venous thromboembolism [see Warnings and Precautions ( 5.4 , 5.5 )] . Hypertension : bevacizumab products can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their health care provider if they experience changes in blood pressure [see Warnings and Precautions ( 5.6 )] . P osterior Reversible Leukoencephalopathy Syndrome : Posterior reversible encephalopathy syndrome (PRES) has been associated with bevacizumab products treatment. Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions ( 5.7 )] . R e nal Injury and Proteinuria : bevacizumab products increase the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment with Avzivi requires regular monitoring of renal function and to contact their health care provider for proteinuria or signs and symptoms of nephrotic syndrome [see Warnings and Precautions ( 5.8 )] . I n f usion-Related Reactions : bevacizumab products can cause infusion-related reactions. Advise patients to contact their health care provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions ( 5.9 )]. C ongestive Heart Failure : bevacizumab products can increase the risk of developing congestive heart failure. Advise patients to contact their health care provider immediately for signs and symptoms of CHF [see Warnings and Precautions ( 5.12 )]. Embryo-Fetal Toxicity : Advise female patients that bevacizumab products may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Avzivi and for 6 months after the last dose [see Use in Specific Populations ( 8.3 )]. Ovarian Failure : bevacizumab products may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment [see Warnings and Precautions ( 5.11 )]. L a c tation : Advise women not to breastfeed during treatment with Avzivi and for 6 months after the last dose [see Use in Specific Populations ( 8.2 )] . Avzivi ® (bevacizumab-tnjn) Manufactured by: Bio-Thera Solutions, Ltd. 11 Kaiyuan Boulevard, Huangpu District Guangzhou, Guangdong Province, China, 510530 U.S. License No. XXXX Avzivi ® is a registered trademark. ©2020 Bio-Thera Solutions, Ltd.

14 CLINICAL STUDIES 14.1 Metastatic Colorectal Cancer Study AVF2107g The safety and efficacy of bevacizumab was evaluated in a double-blind, active-controlled study [AVF2107g (NCT00109070)] in 923 patients with previously untreated mCRC who were randomized (1:1:1) to placebo with bolus-IFL (irinotecan 125 mg/m 2 , fluorouracil 500 mg/m 2 , and leucovorin 20 mg/m 2 given once weekly for 4 weeks every 6 weeks), bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL, or bevacizumab (5 mg/kg every 2 weeks) with fluorouracil and leucovorin. Enrollment to the bevacizumab with fluorouracil and leucovorin arm was discontinued after enrollment of 110 patients in accordance with the protocol-specified adaptive design. Bevacizumab was continued until disease progression or unacceptable toxicity or for a maximum of 96 weeks. The main outcome measure was overall survival (OS). The median age was 60 years; 60% were male, 79% were White, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. The dominant site of disease was extra-abdominal in 56% of patients and was the liver in 38% of patients. The addition of bevacizumab improved survival across subgroups defined by age (<65 years, ≥65 years) and sex. Results are presented in Table 6 and Figure 1. Table 6: Efficacy Results in Study AVF2107g Efficacy Parameter Bevacizumab with bolus-IFL (N=402) Placebo with bolus-IFL (N=411) Overall Survival Median, in months 20.3 15.6 Hazard ratio (95% CI) 0.66 (0.54, 0.81) p-value a <0.001 Progression-Free Survival Median, in months 10.6 6.2 Hazard ratio (95% CI) 0.54 (0.45, 0.66) p-value a <0.001 Overall Response Rate Rate (%) 45% 35% p-value b <0.01 Duration of Response Median, in months 10.4 7.1 a by stratified log-rank test. b by χ 2 test Figure 1: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study A V F 2107g Among the 110 patients randomized to bevacizumab with fluorouracil and leucovorin, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, overall response rate (ORR) was 39%, and median duration of response was 8.5 months. S tudy E3200 The safety and efficacy of bevacizumab were evaluated in a randomized, open-label, active-controlled study [E3200 (NCT00025337)] in 829 patients who were previously treated with irinotecan and fluorouracil for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to FOLFOX4 (Day 1: oxaliplatin 85 mg/m 2 and leucovorin 200 mg/m 2 concurrently, then fluorouracil 400 mg/m 2 bolus followed by 600 mg/m 2 continuously; Day 2: leucovorin 200 mg/m 2 , then fluorouracil 400 mg/m 2 bolus followed by 600 mg/m 2 continuously; every 2 weeks), 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 main outcome measure was OS. The bevacizumab alone arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone. The median age was 61 years; 60% were male, 87% were White, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan with or without fluorouracil for metastatic disease, and 1% received prior irinotecan and fluorouracil as adjuvant therapy. The addition of bevacizumab to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone; median OS was 13.0 months vs. 10.8 months [hazard ratio (HR) 0.75 (95% CI: 0.63, 0.89), p-value of 0.001 stratified log-rank test] with clinical benefit seen in subgroups defined by age (<65 years, ≥65 years) and sex. PFS and ORR based on investigator assessment were higher in patients receiving bevacizumab with FOLFOX4. S tudy TRC-0301 The activity of bevacizumab with fluorouracil (as bolus or infusion) and leucovorin was evaluated in a single arm study [TRC-0301 (NCT00066846)] enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-based chemotherapy. Seventy-three percent of patients received concurrent bolus fluorouracil and leucovorin. One objective partial response was verified in the first 100 evaluable patients for an ORR of 1% (95% CI: 0%, 5.5%). S tudy ML18147 The safety and efficacy of bevacizumab were evaluated in a prospective, randomized, open-label, multinational, controlled study [ML18147 (NCT00700102)] in 820 patients with histologically confirmed mCRC who had progressed on a first-line bevacizumab-containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received bevacizumab for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1) within 3 months after discontinuing bevacizumab as first-line treatment to receive fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). The choice of second-line treatment was contingent upon first-line chemotherapy. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS. A secondary outcome measure was ORR. The median age was 63 years (21 to 84 years); 64% were male, 52% had an ECOG performance status of 1, 44% had an ECOG performance status of 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of bevacizumab as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each arm. The addition of bevacizumab to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of OS and PFS. There was no significant difference in ORR. Results are presented in Table 7 and Figure 2. Table 7: Efficacy Results in Study ML18147 Efficacy Parameter Bevacizumab with Chemotherapy (N=409) Chemotherapy (N=411) Overall Survival a Median, in months 11.2 9.8 Hazard ratio (95% CI) 0.81 (0.69, 0.94) Progression-Free Survival b Median, in months 5.7 4.0 Hazard ratio (95% CI) 0.68 (0.59, 0.78) a p=0.0057 by unstratified log-rank test. b p-value <0.0001 by unstratified log-rank test. Figure 2: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study ML18147 fig-01 fig-02 14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer Lack of efficacy of bevacizumab as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical studies. The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive bevacizumab at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (N=1155) or on a 3-weekly schedule with XELOX (N=1145) or FOLFOX4 alone (N=1151). The main outcome measure was disease free survival (DFS) in patients with stage III colon cancer. The median age was 58 years; 54% were male, 84% were White and 29% were ≥65 years. Eighty-three percent had stage III disease. The addition of bevacizumab to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving bevacizumab with FOLFOX4 or with XELOX. The hazard ratios for DFS were 1.17 (95% CI: 0.98, 1.39) for bevacizumab with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for bevacizumab with XELOX versus FOLFOX4 alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of bevacizumab with FOLFOX4 versus FOLFOX4 alone and bevacizumab with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the bevacizumab-containing arms compared to FOLFOX4 alone in the high-risk stage II cohort. In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either bevacizumab administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of bevacizumab to mFOLFOX6 [HR 0.96 (95% CI: 0.75, 1.22)]. 14.3 First-Line Non–Squamous Non–Small Cell Lung Cancer S tudy E4599 The safety and efficacy of bevacizumab as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study [E4599 (NCT00021060)]. A total of 878 chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6) with or without bevacizumab 15 mg/kg. After completing or discontinuing 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 main outcome measure was duration of survival. The median age was 63 years; 54% were male, 43% were ≥65 years, and 28% had ≥5% weight loss at study entry. Eleven percent had recurrent disease. Of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease. OS was statistically significantly longer for patients receiving bevacizumab with paclitaxel and carboplatin compared with those receiving chemotherapy alone. Median OS was 12.3 months vs. 10.3 months [HR 0.80 (95% CI: 0.68, 0.94), final p-value of 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with bevacizumab with paclitaxel and carboplatin compared to chemotherapy alone. Results are presented in Figure 3. Figure 3: Kaplan-Meier Curves for Duration of Survival in First-Line Non-Squamous Non-Small Cell Lung Cancer in Study E4599 In an exploratory analysis across patient subgroups, the impact of bevacizumab on OS was less robust in the following subgroups: women [HR 0.99 (95% CI: 0.79, 1.25)], patients ≥65 years [HR 0.91 (95% CI: 0.72, 1.14)] and patients with ≥5% weight loss at study entry [HR 0.96 (95% CI: 0.73, 1.26)]. S tudy BO17704 The safety and efficacy of bevacizumab in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo-controlled study [BO17704 (NCT00806923)]. A total of 1043 patients were randomized (1:1:1) to receive cisplatin and gemcitabine with placebo, bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg. The main outcome measure was PFS. Secondary outcome measure was OS. The median age was 58 years; 36% were female and 29% were ≥65 years. Eight percent had recurrent disease and 77% had Stage IV disease. PFS was significantly higher in both bevacizumab-containing arms compared to the placebo arm [HR 0.75 (95% CI: 0.62, 0.91), p-value of 0.0026 for bevacizumab 7.5 mg/kg and HR 0.82 (95% CI: 0.68; 0.98), p-value of 0.0301 for bevacizumab 15 mg/kg]. The addition of bevacizumab to cisplatin and gemcitabine failed to demonstrate an improvement in the duration of OS [HR 0.93 (95% CI: 0.78; 1.11), p-value of 0.420 for bevacizumab 7.5 mg/kg and HR 1.03 (95% CI: 0.86, 1.23), p-value of 0.761 for bevacizumab 15 mg/kg] . fig-03 14.4 Recurrent Glioblastoma S tudy EORTC 26101 The safety and efficacy of bevacizumab were evaluated in a multicenter, randomized (2:1), open-label study in patients with recurrent GBM (EORTC 26101, NCT01290939). Patients with first progression following radiotherapy and temozolomide were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine (90 mg/m 2 every 6 weeks) or lomustine (110 mg/m 2 every 6 weeks) alone until disease progression or unacceptable toxicity. Randomization was stratified by World Health Organization performance status (0 vs. >0), steroid use (yes vs. no), largest tumor diameter (≤40 vs. >40 mm), and institution. The main outcome measure was OS. Secondary outcome measures were investigator-assessed PFS and ORR per the modified Response Assessment in Neuro-oncology (RANO) criteria, health related quality of life (HRQoL), cognitive function, and corticosteroid use. A total of 432 patients were randomized to receive lomustine alone (N=149) or bevacizumab with lomustine (N=283). The median age was 57 years; 24.8% of patients were ≥65 years. The majority of patients with were male (61%); 66% had a WHO performance status score >0; and in 56% the largest tumor diameter was ≤40 mm. Approximately 33% of patients randomized to receive lomustine received bevacizumab following documented progression. No difference in OS (HR 0.91, p -value of 0.4578) was observed between arms; therefore, all secondary outcome measures are descriptive only. PFS was longer in the bevacizumab with lomustine arm [HR 0.52 (95% CI: 0.41, 0.64)] with a median PFS of 4.2 months in the bevacizumab with lomustine arm and 1.5 months in the lomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the bevacizumab with lomustine arm discontinued corticosteroids (23% vs. 12%). S tudy AVF3708g and Study NCI 06-C-0064E The efficacy and safety of bevacizumab 10 mg/kg every 2 weeks in patients with previously treated GBM were evaluated in one single arm single center study (NCI 06-C-0064E) and a randomized noncomparative multicenter study [AVF3708g (NCT00345163)]. Response rates in both studies were evaluated based on modified WHO criteria that considered corticosteroid use. In AVF3708g, the response rate was 25.9% (95% CI: 17%, 36.1%) with a median duration of response of 4.2 months (95% CI: 3, 5.7). In Study NCI 06-C-0064E, the response rate was 19.6% (95% CI: 10.9%, 31.3%) with a median duration of response of 3.9 months (95% CI: 2.4, 17.4). 14.5 Metastatic Renal Cell Carcinoma S tudy BO17705 The safety and efficacy of bevacizumab were evaluated in patients with treatment-naïve mRCC in a multicenter, randomized, double-blind, international study [BO17705 (NCT00738530)] comparing interferon alfa and bevacizumab versus interferon alfa and placebo. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks; N=327) or placebo (every 2 weeks; N=322) with interferon alfa (9 MIU subcutaneously three times weekly for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS. The median age was 60 years (18 to 82 years); 70% were male and 96% were White. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3−5), and 7% missing. PFS was statistically significantly prolonged among patients receiving bevacizumab compared to placebo; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI: 0.49, 0.72), p-value <0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p-value <0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the patients receiving bevacizumab with interferon alfa and 21 months in patients receiving interferon alone [HR 0.86, (95% CI: 0.72, 1.04)]. Results are presented in Figure 4. Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Metastatic Renal Cell Carcinoma in Stud y BO17705 fig-04 14.6 Persistent, Recurrent, or Metastatic Cervical Cancer S tudy GOG-0240 The safety and efficacy of bevacizumab were evaluated in patients with persistent, recurrent, or metastatic cervical cancer in a randomized, four-arm, multicenter study comparing bevacizumab with chemotherapy versus chemotherapy alone [GOG-0240 (NCT00803062)]. A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab, or paclitaxel and topotecan with or without bevacizumab. The dosing regimens for bevacizumab, paclitaxel, cisplatin and topotecan were as follows: Day 1: Paclitaxel 135 mg/m 2 over 24 hours, Day 2: cisplatin 50 mg/m 2 with bevacizumab; Day 1: Paclitaxel 175 mg/m 2 over 3 hours, Day 2: cisplatin 50 mg/m 2 with bevacizumab; Day 1: Paclitaxel 175 mg/m 2 over 3 hours with cisplatin 50 mg/m 2 with bevacizumab; Day 1: Paclitaxel 175 mg/m 2 over 3 hours with bevacizumab, Days 1-3: topotecan IV 0.75 mg/m 2 over 30 minutes Patients were treated until disease progression or unacceptable adverse reactions. The main outcome measure was OS. Secondary outcome measures included ORR. The median age was 48 years (20 to 85 years). Of the 452 patients randomized at baseline, 78% of patients were White, 80% had received prior radiation, 74% had received prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval (PFI) of less than 6 months. Patients had a GOG performance status of 0 (58%) or 1 (42%). Demographic and disease characteristics were balanced across arms. Results are presented in Figure 5 and Table 8. Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical Cancer in Study GOG-0240 Table 8: Efficacy Results in Study GOG-0240 Efficacy Parameter Bevacizumab with Chemotherapy (N=227) Chemotherapy (N=225) Overall Survival Median, in months a 16.8 12.9 Hazard ratio (95% CI) 0.74 (0.58, 0.94) p-value b 0.0132 a Kaplan-Meier estimates. b log-rank test (stratified). The ORR was higher in patients who received bevacizumab with chemotherapy [45% (95% CI: 39, 52)] compared to patients who received chemotherapy alone [34% (95% CI: 28,40)]. Table 9: Efficacy Results in Study GOG-0240 Efficacy Parameter Topotecan and Paclitaxel with or without bevacizumab (N=223) Cisplatin and Paclitaxel with or without bevacizumab (N=229) Overall Survival Median, in months a 13.3 15.5 Hazard ratio (95% CI) 1.15 (0.91, 1.46) p-value 0.23 a Kaplan-Meier estimates. The HR for OS with bevacizumab with cisplatin and paclitaxel as compared to cisplatin and paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The HR for OS with bevacizumab with topotecan and paclitaxel as compared to topotecan and paclitaxel alone was 0.76 (95% CI: 0.55, 1.06). fig-05 14.7 Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Study MO22224 The safety and efficacy of bevacizumab were evaluated in a multicenter, open-label, randomized study [MO22224 (NCT00976911)] comparing bevacizumab with chemotherapy versus 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 (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following chemotherapy regimens at the discretion of the investigator: paclitaxel (80 mg/m 2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m 2 on day 1 every 4 weeks; or topotecan 4 mg/m 2 on days 1, 8 and 15 every 4 weeks or 1.25 mg/m 2 on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS. The median age was 61 years (25 to 84 years) and 37% of patients were ≥65 years. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥2 times ULN and 31% had ascites at baseline. Seventy-three percent had a PFI of 3 months to 6 months and 27% had PFI of <3 months. ECOG performance status was 0 for 59%, 1 for 34% and 2 for 7% of the patients. The addition of bevacizumab to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. Results for the ITT population are presented in Table 10 and Figure 6. Results for the separate chemotherapy cohorts are presented in Table 11. Table 10: Efficacy Results in Study MO22224 Efficacy Parameter Bevacizumab with Chemotherapy (N=179) Chemotherapy (N=182) Progression-Free Survival per Investigator Median (95% CI), in months 6.8 (5.6, 7.8) 3.4 (2.1, 3.8) HR (95% CI) a 0.38 (0.30, 0.49) p-value b <0.0001 Overall Survival Median (95% CI), in months 16.6 (13.7, 19.0) 13.3 (11.9, 16.4) HR (95% CI) a 0.89 (0.69, 1.14) Overall Response Rate Number of Patients with Measurable Disease at Baseline 142 144 Rate, % (95% CI) 28% (21%, 36%) 13% (7%, 18%) Duration of Response Median, in months 9.4 5.4 a per stratified Cox proportional hazards model b per stratified log-rank test Figure 6: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Platinum- Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study MO22224 Table 11: Efficacy Results in Study MO22224 by Chemotherapy Efficacy Parameter Paclitaxel Topotecan Pegylated Liposomal Doxorubicin Bevacizumab with Chemotherapy (N=60) Chemotherapy (N=55) Bevacizumab with Chemotherapy (N=57) Chemotherapy (N=63) Bevacizumab with Chemotherapy (N=62) Chemotherapy (N=64) Progression-Free Survival per Investigator Median, in months (95% CI) 9.6 (7.8, 11.5) 3.9 (3.5, 5.5) 6.2 (5.3, 7.6) 2.1 (1.9, 2.3) 5.1 (3.9, 6.3) 3.5 (1.9, 3.9) Hazard ratio a (95% CI) 0.47 (0.31, 0.72) 0.24 (0.15, 0.38) 0.47 (0.32, 0.71) Overall Survival Median, in months (95% CI) 22.4 (16.7, 26.7) 13.2 (8.2, 19.7) 13.8 (11.0, 18.3) 13.3 (10.4, 18.3) 13.7 (11.0, 18.3) 14.1 (9.9, 17.8) Hazard ratio a (95% CI) 0.64 (0.41, 1.01) 1.12 (0.73, 1.73) 0.94 (0.63, 1.42) Overall Response Rate Number of patients with measurable disease at baseline 45 43 46 50 51 51 Rate, % (95% CI) 53 (39, 68) 30 (17, 44) 17 (6, 28) 2 (0, 6) 16 (6, 26) 8 (0, 15) Duration of Response Median, in months 11.6 6.8 5.2 NE 8.0 4.6 a per stratified Cox proportional hazards model NE=Not Estimable fig-06

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. ( 8.2 ) See 17 for PATIENT COUNSELING INFORMATION. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Avzivi has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. 8.1 Pregnancy R isk Summary Based on findings from animal studies and their mechanism of action [see Clinical Pharmacology ( 12.1 )], 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 1 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 (see Data) . 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. Data Animal Data Pregnant rabbits dosed with 10 mg/kg to 100 mg/kg bevacizumab (approximately 1 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. 8.2 Lactation R isk Summary No data are available regarding the presence of bevacizumab products in human milk, the effects on the breast fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Avzivi and for 6 months after the last dose. 8.3 Females and Males of Reproductive Potential Contraception Females Bevacizumab products may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with Avzivi and for 6 months after the last dose. Infertility Females Bevacizumab products increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to the first-dose of Avzivi. Long-term effects of bevacizumab products on fertility are not known. In a clinical study of 179 premenopausal women randomized to receive chemotherapy with or without bevacizumab, the incidence of ovarian failure was higher in patients who received bevacizumab with chemotherapy (34%) compared to patients who received chemotherapy alone (2%). After discontinuing bevacizumab with chemotherapy, recovery of ovarian function occurred in 22% of these patients [see Warnings and Precautions ( 5.11 ), Adverse Reactions ( 6.1 ) ] . 8.4 Pediatric Use The safety and effectiveness of Avzivi 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. 8.5 Geriatric Use 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%) [see Warnings and Precautions ( 5.4 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Avzivi (bevacizumab-tnjn) injection is a clear to slightly opalescent, colorless to pale brown, sterile solution for intravenous infusion supplied as single-dose vials in the following strengths: 100 mg/4 mL (25 mg/mL): carton of one vial (NDC 82143-001-01) 400 mg/16 mL (25 mg/mL) : carton of one vial (NDC 82143-002-01) Store refrigerated at 2 o C to 8 o C (36 o F to 46 o F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.