Vegzelma

1 INDICATIONS AND USAGE VEGZELMA 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 : VEGZELMA 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 carboplatin and paclitaxel, followed by VEGZELMA as a single agent, for stage III or IV disease following initial surgical resection ( 1.6 ) 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 ) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by VEGZELMA as a single agent, for platinum-sensitive recurrent disease ( 1.6 ) 1.1 Metastatic Colorectal Cancer VEGZELMA, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC). VEGZELMA, 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 : VEGZELMA 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 VEGZELMA, 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 VEGZELMA is indicated for the treatment of recurrent glioblastoma (GBM) in adults. 1.4 Metastatic Renal Cell Carcinoma VEGZELMA, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC). 1.5 Persistent, Recurrent, or Metastatic Cervical Cancer VEGZELMA, 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 VEGZELMA, in combination with carboplatin and paclitaxel, followed by VEGZELMA 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. VEGZELMA, 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. VEGZELMA, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by VEGZELMA 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 VEGZELMA 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 and 2.9 ) 2.1 Important Administration Information Withhold for at least 28 days prior to elective surgery. Do not administer VEGZELMA until at least 28 days following major surgery and until adequate wound healing. 2.2 Metastatic Colorectal Cancer The recommended dosage when VEGZELMA 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 VEGZELMA 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 i …

3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to 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 )

4 CONTRAINDICATIONS None. None ( 4 )

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 CELLTRION USA, Inc. at 1-800-560-9414 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, AVF4095, GOG-0213, and GOG-0218) or another cancer 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 …

7 DRUG INTERACTIONS Effects of VEGZELMA 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk 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 Risk 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 VEGZELMA 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 VEGZELMA and for 6 months after the last dose. Infertility Females Bevacizumab products increase 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 VEGZELMA. 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 bevacizumab products in pediatric patients have not been established. In published literature …

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.

11 DESCRIPTION Bevacizumab-adcd is a vascular endothelial growth factor inhibitor. Bevacizumab-adcd is a recombinant humanized monoclonal IgG1 antibody that contains human framework regions and murine complementarity-determining regions. Bevacizumab-adcd has an approximate molecular weight of 149 kDa. Bevacizumab-adcd is produced in a mammalian cell (Chinese Hamster Ovary) expression system. VEGZELMA (bevacizumab-adcd) injection is a sterile, preservative-free, clear to opalescent, colorless to pale brown solution in a single-dose vial for intravenous use. VEGZELMA contains bevacizumab-adcd at a concentration of 25 mg/mL in either 100 mg/4 mL or 400 mg/16 mL single-dose vials. Each mL of solution contains 25 mg bevacizumab-adcd, 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 6.2.

16 HOW SUPPLIED/STORAGE AND HANDLING VEGZELMA (bevacizumab-adcd) injection is a clear to opalescent, colorless to pale brown, sterile solution for intravenous infusion supplied in a single-dose vial packaged within cartons in the following strengths and packaging configurations: 100 mg/4 mL (25 mg/mL): carton of one vial (NDC 72606-011-01); carton of 10 vials (NDC 72606-011-10). 400 mg/16 mL (25 mg/mL): carton of one vial (NDC 72606-012-01); carton of 10 vials (NDC 72606-012-10). Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.