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

5 WARNINGS AND PRECAUTIONS Hemorrhage : Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in patients who have received ZALTRAP. Do not administer ZALTRAP to patients with severe hemorrhage. ( 5.1 ) Gastrointestinal Perforation : Discontinue ZALTRAP therapy in patients who experience GI perforation. ( 5.2 ) Impaired Wound Healing : Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer for at least 4 weeks following major surgery and until wounds have adequately healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established. ( 5.3 ) Fistula Formation : Discontinue ZALTRAP if fistula occurs. ( 2.2 , 5.4 ) Hypertension : Monitor blood pressure and treat hypertension. Temporarily suspend ZALTRAP if hypertension is not controlled. Discontinue ZALTRAP if hypertensive crisis develops. ( 2.2 , 5.5 ) Arterial Thromboembolic Events (ATE) : Discontinue ZALTRAP if ATE develops. ( 5.6 ) Proteinuria : Monitor urine protein. Suspend ZALTRAP for proteinuria of 2 grams per 24 hours or more. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) develops. ( 2.2 , 5.7 ) Neutropenia and Neutropenic Complications : Delay administration of ZALTRAP/FOLFIRI until neutrophil count is 1.5 × 10 9 /L or higher. ( 5.8 ) Diarrhea and Dehydration : Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely. ( 5.9 , 8.5 ) Reversible Posterior Leukoencephalopathy Syndrome : Discontinue ZALTRAP. ( 5.10 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) was reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2) ] . 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2) ] . 5.3 Impaired Wound Healing Grade 3 impaired wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen. Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer ZALTRAP for at least 4 weeks after major surgery and until wounds have adequately healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been establi…

4 CONTRAINDICATIONS None. None ( 4 )

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) ] .

8.1 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).

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 …