Avzivi tnjn

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.

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 hemop…

5 WARNINGS AND PRECAUTIONS • Gastrointestinal Perforations and Fistula : Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ. ( 5.1 ) • Surgery and Wound Healing Complications : In patients who experience wound healing complications during Avzivi treatment, withhold Avzivi until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer Avzivi for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complication has not been established. Discontinue for wound healing complication of necrotizing fasciitis. ( 5.2 ) • Hemorrhage : Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage. ( 5.3 ) • Arterial Thromboembolic Events (ATE) : Discontinue for severe ATE. ( 5.4 ) • Venous Thromboembolic Events (VTE) : Discontinue for Grade 4 VTE. ( 5.5 ) • Hypertension : Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. ( 5.6 ) • Posterior Reversible Encephalopathy Syndrome (PRES) : Discontinue. ( 5.7 ) • Renal Injury and Proteinuria : Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. ( 5.8 ) • Infusion-Related Reactions : Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. ( 5.9 ) • Embryo-Fetal Toxicity : May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.10 , 8.1 , 8.3 ) • Ovarian Failure : Advise females of the potential risk. ( 5.11 , 8.3 ) • Congestive Heart Failure (CHF) : Discontinue Avzivi in patients who develop CHF. ( 5.12 ) 5.1 Gastrointestinal Perforations and Fistulae Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions ( 6.1 )] . Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. The incidence ranged from <1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy. Avoid Avzivi in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ . 5.2 Surgery and Wound Healing Complications In a controlled clinical study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing…

4 CONTRAINDICATIONS None. None. ( 4 )

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.

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:…