ZALTRAP

1 INDICATIONS AND USAGE ZALTRAP, in combination with fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. ZALTRAP, a vascular endothelial growth factor inhibitor, in combination with fluorouracil, leucovorin, irinotecan (FOLFIRI), is indicated for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. ( 1 )

2 DOSAGE AND ADMINISTRATION 4 mg per kg as an intravenous infusion over 1 hour every 2 weeks. ( 2.1 , 2.3 ) Do not administer as an intravenous push or bolus. ( 2.3 ) 2.1 Recommended Dose and Schedule The recommended dosage of ZALTRAP is 4 mg per kg of actual body weight as an intravenous infusion over 1 hour every two weeks in combination with FOLFIRI until disease progression or unacceptable toxicity. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment. Refer to prescribing information for irinotecan, fluorouracil, and leucovorin for the recommended dosage and dosage modifications for these drugs. 2.2 Dosage Modifications for Adverse Reactions Discontinue ZALTRAP for: Severe hemorrhage [see Warnings and Precautions (5.1) ] Gastrointestinal perforation [see Warnings and Precautions (5.2) ] Impaired wound healing [see Warnings and Precautions (5.3) ] Fistula formation [see Warnings and Precautions (5.4) ] Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5) ] Arterial thromboembolic events (ATE) [see Warnings and Precautions (5.6) ] Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7) ] Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10) ] Temporarily suspend ZALTRAP: At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3) ]. For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5) ] . For proteinuria of 2 grams per 24 hours or more. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7) ] . 2.3 Preparation and Administration Preparation Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to achieve a final concentration of 0.6 mg/mL to 8 mg/mL. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 8 hours. Discard any unused portion left in the infusion bag. Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2-micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous push or bolus. Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: PVC containing DEHP DEHP free PVC containing trioctyl-trimellitate (TOTM) polypropylene polyethylene lined PVC polyurethane

3 DOSAGE FORMS AND STRENGTHS ZALTRAP is a clear, colorless to pale-yellow solution available as: Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial Injection: 200 mg/8 mL (25 mg/mL) solution in a single-dose vial Injection: 100 mg/4 mL (25 mg/mL) and 200 mg/8 mL (25 mg/mL) solution 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: Hemorrhage [see Warnings and Precautions (5.1) ] Gastrointestinal Perforation [see Warnings and Precautions (5.2) ] Impaired Wound Healing [see Warnings and Precautions (5.3) ] Fistula Formation [see Warnings and Precautions (5.4) ] Hypertension [see Warnings and Precautions (5.5) ] Arterial Thromboembolic Events [see Warnings and Precautions (5.6) ] Proteinuria [see Warnings and Precautions (5.7) ] Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8) ] Diarrhea and Dehydration [see Warnings and Precautions (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥20% incidence) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR (EFC102621) [see Clinical Studies (14) ]. Patients received ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two weeks (one cycle) in combination with FOLFIRI. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI. The most common Grade 3–4 adverse reactions (≥5%) in the ZALTRAP/FOLFIRI arm were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria. The ZALTRAP dose was reduced and/or omitted in 17% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI. The most common adverse reactions (≥20%) in the ZALTRAP/FOLFIRI arm were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. Adverse reactions and laboratory abnormalities that occurred in ≥5% (all grades) of patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients who received ZALTRAP/FOLFIRI compared to those who received placebo/FOLFIRI in VELOUR are shown in Table 1. VELOUR was not designed to demonstrate a statistically significant difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to placebo/FOLFIRI for any adverse reactions listed below. Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR Primary System Organ Class Preferred Term ZALTRAP/ FOLFIRI (N=611) Placebo/ FOLFIRI (N=605) All grades (%) Grades 3–4 (%) All grades (%) Grades 3–4 (%) Note: Adverse Reactions are reported using MedDRA version 13.1 and graded using NCI CTC version 3.0 Blood and lymphatic system disorders Leukopenia 78 16 72 12 Neutropenia 67 37 57 30 Thrombocytopenia 48 3 35 2 Gastrointestinal disorders Diarrhea 69 19 57 8 Stomatitis 50 13 33 5 Abdominal Pain 27 4 24 2 Abdominal Pain Upper 11 1 8 1 Hemorrhoids 6 0 2 0 Rectal Hemorrhage 5 0.7 2 0.5 Proctalgia 5 0.3 2 0.3 Investigations AST increased 62 3 54 2 ALT increased 50 3 39 2 Weight decreased 32 3 14 0.8 Renal and urinary disorders Proteinuria Compilation of clinical and …

7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic interactions were found between ziv-aflibercept and irinotecan/SN-38 or fluorouracil [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , ZALTRAP can cause fetal harm when administered to pregnant women. There is insufficient data in pregnant women exposed to ZALTRAP to assess the risks. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose (see Data ) . 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 In pregnant rabbits, administration of ziv-aflibercept during the period of organogenesis resulted in an increase in postimplantation loss and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and anal atresia), visceral (heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs, supernumerary arches and ribs, and incomplete ossification) at doses greater than or equal to 3 mg per kg, administered once every 3 days (approximately 0.3 times the human exposure at the 4 mg per kg dose based on AUC). 8.2 Lactation Risk Summary There are no data on the presence of ziv-aflibercept in human milk, or the effects of ziv-aflibercept on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose. 8.3 Females and Males of Reproductive Potential ZALTRAP can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating ZALTRAP [see Use in Specific Populations (8.1) ] . Contraception Females Based on data from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use effective contraception during treatment with ZALTRAP and for 3 months following the last dose. Infertility Advise female and male patients of reproductive potential that ZALTRAP may impair reproductive function and fertility [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Safety and efficacy were assessed, but not established in a dose-escalation, safety, and tolerability study (NCT00622414) in 21 patients with solid tumors 2 to 21 years of age (median age 12.9). The mean elimination half-life of free ziv-aflibercept determined after the first dose in 8 pediatric patients aged 5 to 17 years was within the range of values previously observed in adults. The maximum tolerated dose based on body weight in these pediatric patients was lower than the dose known to be safe and effective in adults with mCRC. Juvenile Animal Toxicity Data Weekly/every-two-weeks intravenous administration of ziv-aflibercept at dose of 3 mg per kg (approximately 0.6 times the human exposure at the 4 mg per kg dose based on AUC) to growing young adult (sexually mature) cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity (atrophy/loss of the septum and/or turbinates), kidney (glomerulopathy with inflammation), ovary (decreased number of maturing follicles, granulosa cells, and/or theca cells), and adrenal gland (decreased vacuolation with inflammation). In another study in sexually immature cynomolgus monkeys (treated intravenously for 3 mon …

12.1 Mechanism of Action Ziv-aflibercept acts as a soluble receptor that binds to human VEGF-A (equilibrium dissociation constant K D of 0.5 pM for VEGF-A 165 and 0.36 pM for VEGF-A 121 ), to human VEGF-B (K D of 1.92 pM), and to human PlGF (K D of 39 pM for PlGF-2). By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability. In animals, ziv-aflibercept was shown to inhibit the proliferation of endothelial cells, thereby inhibiting the growth of new blood vessels. Ziv-aflibercept inhibited the growth of xenotransplanted colon tumors in mice.

11 DESCRIPTION Ziv-aflibercept is a vascular endothelial growth factor inhibitor. It is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgG1. Ziv-aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Ziv-aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. ZALTRAP (ziv-aflibercept) injection is a sterile, clear, colorless to pale-yellow, non-pyrogenic, preservative-free, solution for intravenous use. ZALTRAP is supplied in single-dose vials of 100 mg/4 mL and 200 mg/8 mL formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (1 mg/mL), sodium chloride (5.84 mg/mL), sodium citrate (1.45 mg/mL), sodium phosphate (0.8 mg/mL), and sucrose (200 mg/mL), in Water for Injection, USP, at a pH of 6.2.

16 HOW SUPPLIED/STORAGE AND HANDLING ZALTRAP (ziv-aflibercept) injection is a clear, colorless to pale-yellow solution supplied in single-dose vials with a concentration of 25 mg/mL. NDC 0024-5840-01: carton containing one single-dose vial of 100 mg/4 mL (25 mg/mL) NDC 0024-5841-01: carton containing one single-dose vial of 200 mg/8 mL (25 mg/mL) Store ZALTRAP vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Keep the vials in the original outer carton to protect from light. Discard unused portion.