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  • ZALTRAP AFLIBERCEPT 100 mg/4mL sanofi-aventis U.S. LLC
FDA Drug information

ZALTRAP

Read time: 2 mins
Marketing start date: 20 Jul 2024

Summary of product characteristics


Adverse Reactions

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 laboratory data 62 8 41 1 Serum creatinine increased 23 0 19 0.5 General disorders and administration site conditions Fatigue 48 13 39 8 Asthenia 18 5 13 3 Vascular disorders Hypertension 41 19 11 1.5 Metabolism and nutrition disorders Decreased Appetite 32 3 24 2 Dehydration 9 4 3 1 Respiratory, thoracic and mediastinal disorders Epistaxis 28 0.2 7 0 Dysphonia 25 0.5 3 0 Dyspnea 12 0.8 9 0.8 Oropharyngeal Pain 8 0.2 3 0 Rhinorrhea 6 0 2 0 Nervous system disorders Headache 22 2 9 0.3 Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysesthesia Syndrome 11 3 4 0.5 Skin Hyperpigmentation 8 0 3 0 Infections Urinary Tract Infection 9 0.8 6 0.8 Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for antiproduct antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZALTRAP. 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. Musculoskeletal and connective tissue disorders : Osteonecrosis of the jaw Cardiac disorders : Cardiac failure, ejection fraction decreased Vascular disorders : Arterial (including aortic) aneurysms, dissections, and rupture

Contraindications

4 CONTRAINDICATIONS None. None ( 4 )

Description

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.

Dosage And Administration

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

Indications And Usage

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 )

Adverse Reactions Table

Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR
Primary System Organ Class Preferred TermZALTRAP/ 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
Leukopenia78167212
Neutropenia67375730
Thrombocytopenia483352
Gastrointestinal disorders
Diarrhea6919578
Stomatitis5013335
Abdominal Pain274242
Abdominal Pain Upper11181
Hemorrhoids6020
Rectal Hemorrhage50.720.5
Proctalgia50.320.3
Investigations
AST increased623542
ALT increased503392
Weight decreased323140.8
Renal and urinary disorders
ProteinuriaCompilation of clinical and laboratory data628411
Serum creatinine increased230190.5
General disorders and administration site conditions
Fatigue4813398
Asthenia185133
Vascular disorders
Hypertension4119111.5
Metabolism and nutrition disorders
Decreased Appetite323242
Dehydration9431
Respiratory, thoracic and mediastinal disorders
Epistaxis280.270
Dysphonia250.530
Dyspnea120.890.8
Oropharyngeal Pain80.230
Rhinorrhea6020
Nervous system disorders
Headache22290.3
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysesthesia Syndrome11340.5
Skin Hyperpigmentation8030
Infections
Urinary Tract Infection90.860.8

Drug Interactions

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) ] .

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of 6 mg per kg intravenous ZALTRAP every three weeks on QTc interval was evaluated in 87 patients with solid tumors in a randomized, placebo-controlled study. No large changes in the mean QT interval from baseline (i.e., greater than 20 ms as corrected for placebo) based on Fridericia correction method were detected in the study. However, a small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded due to limitations of the study design. 12.3 Pharmacokinetics Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISA). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2 mg per kg to 9 mg per kg. Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg per kg every two weeks. Elimination Following a dose of 4 mg per kg every two weeks administered intravenously, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4–7 days). Specific Populations Based on a population pharmacokinetic analysis, age, race, and sex did not have a clinically important effect on the exposure of free ziv-aflibercept. Patients weighing ≥100 kg had a 29% increase in systemic exposure compared to patients weighing 50 to 100 kg. Patients with hepatic impairment Based on a population pharmacokinetic analysis which included patients with mild (total bilirubin >1 to 1.5 times ULN and any AST, n=63) and moderate (total bilirubin >1.5 to 3 times ULN and any AST, n=5) hepatic impairment, there was no effect of total bilirubin, AST, and alanine aminotransferase on the clearance of free ziv-aflibercept. There are no data available for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). Patients with renal impairment Based on a population pharmacokinetic analysis which included patients with mild (CL CR 50–80 mL/min, n=549), moderate (CL CR 30–50 mL/min, n=96), and severe renal impairment (CL CR <30 mL/min, n=5), there was no clinically important effect of creatinine clearance on the clearance of free ziv-aflibercept. Drug Interaction Studies No clinically meaningful interaction was found between ziv-aflibercept and irinotecan or fluorouracil based on cross-study comparisons and population pharmacokinetic analyses.

Mechanism Of Action

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.

Pharmacodynamics

12.2 Pharmacodynamics Cardiac Electrophysiology The effect of 6 mg per kg intravenous ZALTRAP every three weeks on QTc interval was evaluated in 87 patients with solid tumors in a randomized, placebo-controlled study. No large changes in the mean QT interval from baseline (i.e., greater than 20 ms as corrected for placebo) based on Fridericia correction method were detected in the study. However, a small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded due to limitations of the study design.

Pharmacokinetics

12.3 Pharmacokinetics Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISA). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2 mg per kg to 9 mg per kg. Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg per kg every two weeks. Elimination Following a dose of 4 mg per kg every two weeks administered intravenously, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4–7 days). Specific Populations Based on a population pharmacokinetic analysis, age, race, and sex did not have a clinically important effect on the exposure of free ziv-aflibercept. Patients weighing ≥100 kg had a 29% increase in systemic exposure compared to patients weighing 50 to 100 kg. Patients with hepatic impairment Based on a population pharmacokinetic analysis which included patients with mild (total bilirubin >1 to 1.5 times ULN and any AST, n=63) and moderate (total bilirubin >1.5 to 3 times ULN and any AST, n=5) hepatic impairment, there was no effect of total bilirubin, AST, and alanine aminotransferase on the clearance of free ziv-aflibercept. There are no data available for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). Patients with renal impairment Based on a population pharmacokinetic analysis which included patients with mild (CL CR 50–80 mL/min, n=549), moderate (CL CR 30–50 mL/min, n=96), and severe renal impairment (CL CR <30 mL/min, n=5), there was no clinically important effect of creatinine clearance on the clearance of free ziv-aflibercept. Drug Interaction Studies No clinically meaningful interaction was found between ziv-aflibercept and irinotecan or fluorouracil based on cross-study comparisons and population pharmacokinetic analyses.

Effective Time

20201125

Version

25

Dosage Forms And Strengths

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 )

Spl Product Data Elements

ZALTRAP ziv-aflibercept AFLIBERCEPT AFLIBERCEPT SUCROSE SODIUM CHLORIDE TRISODIUM CITRATE DIHYDRATE CITRIC ACID MONOHYDRATE POLYSORBATE 20 SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER ZALTRAP ziv-aflibercept AFLIBERCEPT AFLIBERCEPT SUCROSE SODIUM CHLORIDE TRISODIUM CITRATE DIHYDRATE CITRIC ACID MONOHYDRATE POLYSORBATE 20 SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

Animal Pharmacology And Or Toxicology

13.2 Animal Toxicology and/or Pharmacology Repeated administration of ziv-aflibercept resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, ziv-aflibercept administration reduced fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile strength.

Carcinogenesis And Mutagenesis And Impairment Of Fertility

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept. Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were present in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 0.6 times the AUC in patients at the 4 mg per kg dose.

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept. Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were present in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 0.6 times the AUC in patients at the 4 mg per kg dose. 13.2 Animal Toxicology and/or Pharmacology Repeated administration of ziv-aflibercept resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, ziv-aflibercept administration reduced fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile strength.

Application Number

BLA125418

Brand Name

ZALTRAP

Generic Name

ziv-aflibercept

Product Ndc

0024-5840

Product Type

HUMAN PRESCRIPTION DRUG

Route

INTRAVENOUS

Package Label Principal Display Panel

PRINCIPAL DISPLAY PANEL - 100 mg/4 mL Vial Carton NDC 0024-5840-01 ZALTRAP ® (ziv-aflibercept) Injection for Intravenous Infusion 100 mg/4 mL (25 mg/mL) For intravenous infusion only. Not to be administered by other routes. Hyperosmotic, must be diluted. Single-dose vial. Discard unused portion Rx ONLY SANOFI PRINCIPAL DISPLAY PANEL - 100 mg/4 mL Vial Carton

Spl Unclassified Section

Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY U.S. License No. 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. ©2020 sanofi-aventis U.S. LLC

Information For Patients

17 PATIENT COUNSELING INFORMATION Hemorrhage Inform patients that ZALTRAP can cause severe bleeding and advise patients to contact their healthcare provider for bleeding or symptoms of bleeding, including lightheadedness [see Warnings and Precautions (5.1) ] . Gastrointestinal Perforation and Fistula Formation Advise patients to immediately contact their healthcare provider for signs and symptoms of gastrointestinal perforation or fistula [see Warnings and Precautions (5.2 , 5.4) ] . Impaired Wound Healing Advise patients that ZALTRAP may impair wound healing. Instruct patients to discuss any planned surgical procedure (including tooth extractions) with all their healthcare providers [see Warnings and Precautions (5.3) ] . Hypertension Inform patients that ZALTRAP can cause or exacerbate existing hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5) ] . Arterial Thromboembolic Events Inform patients of an increased risk of ATE [see Warnings and Precautions (5.6) ] . Proteinuria Advise patients that they will need to undergo regular laboratory tests to monitor protein in their urine [see Warnings and Precautions (5.7) ] . Neutropenia and Neutropenic Complications Advise patients to notify their healthcare provider of fever or other signs of infection [see Warnings and Precautions (5.8) ] . Diarrhea and Dehydration Advise patients to notify their healthcare provider of severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.9) ] . Posterior Reversible Leukoencephalopathy Syndrome Advise patients to immediately contact their healthcare provider for new onset or worsening neurological function [see Warnings and Precautions (5.10) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential: of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11) , Use in Specific Populations (8.1) ] . to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.3) ] . Lactation Advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.2) ] . Aneurysms and Artery Dissections Advise patients to notify their healthcare provider if they have or have had an aneurysm (swelling/enlargement and weakening of part of a blood vessel) or artery dissection (tear in a blood vessel wall) [see Adverse Reactions (6.3) ] .

Clinical Studies

14 CLINICAL STUDIES The efficacy of ZALTRAP was evaluated in VELOUR (NCT00561470), a randomized (1:1), double-blind, placebo-controlled study in patients with mCRC who are resistant to or have progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab. Patients were randomized to receive either ZALTRAP 4 mg per kg intravenously over 1 hour on day 1 or placebo in combination with FOLFIRI (irinotecan 180 mg/m 2 intravenously over 90 minutes and leucovorin [dl racemic] 400 mg/m 2 intravenously over 2 hours at the same time on day 1 using a Y-line, followed by fluorouracil 400 mg/m 2 as an intravenous bolus and then by fluorouracil 2400 mg/m 2 as a continuous intravenous infusion over 46 hours). The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. Randomization was stratified by the Eastern Cooperative Oncology Group performance status (PS) (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR). Demographics characteristics were similar between treatment arms. A total of 1226 patients were randomized, 612 to the ZALTRAP arm and 614 to the placebo arm. The median age was 61 years, 59% were men, 87% were White, 7% were Asian, 3.5% were Black, and 98% had a baseline ECOG PS of 0 or 1. Among the 1226 randomized patients, 89% and 90% of patients treated with placebo/FOLFIRI and ZALTRAP/FOLFIRI, respectively, received prior oxaliplatin-based combination chemotherapy in the metastatic/advanced setting. A total of 346 patients (28%) received bevacizumab in combination with the prior oxaliplatin-based treatment. Efficacy results are summarized in Figure 1 and Table 2. Figure 1: Kaplan-Meier Curves of Overall Survival for VELOUR Table 2: Main Efficacy Outcome Measures for VELOUR PFS (based on tumor assessment by the IRC): Significance threshold is set to 0.0001. ZALTRAP/FOLFIRI N=612 Placebo/FOLFIRI N=614 Overall Survival Number of deaths, n (%) 403 (65.8%) 460 (74.9%) Median overall survival (95% CI) (months) 13.50 (12.52, 14.95) 12.06 (11.07, 13.08) Stratified Hazard ratio (95% CI) 0.817 (0.714, 0.935) Stratified Log-Rank test p-value 0.0032 Progression Free Survival (PFS) Number of events, n (%) 393 (64.2%) 454 (73.9%) Median PFS (95% CI) (months) 6.90 (6.51, 7.20) 4.67 (4.21, 5.36) Stratified Hazard ratio (95% CI) 0.758 (0.661, 0.869) Stratified Log-Rank test p-value Stratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no) 0.00007 Overall Response Rate (ORR) ORR (CR+PR) (95% CI) Overall objective response rate by IRC 19.8% (16.4%, 23.2%) 11.1% (8.5%, 13.8%) Stratified Cochran-Mantel-Haenszel test p-value 0.0001 Planned subgroup analyses for overall survival based on stratification factors at randomization yielded an HR of 0.86 (95% CI: 0.68, 1.1) in patients who received prior bevacizumab and an HR of 0.79 (95% CI: 0.67, 0.93) in patients without prior bevacizumab exposure. Figure 1

Clinical Studies Table

Table 2: Main Efficacy Outcome Measures for VELOURPFS (based on tumor assessment by the IRC): Significance threshold is set to 0.0001.
ZALTRAP/FOLFIRI N=612Placebo/FOLFIRI N=614
Overall Survival
Number of deaths, n (%)403 (65.8%)460 (74.9%)
Median overall survival (95% CI) (months)13.50 (12.52, 14.95)12.06 (11.07, 13.08)
Stratified Hazard ratio (95% CI)0.817 (0.714, 0.935)
Stratified Log-Rank test p-value0.0032
Progression Free Survival (PFS)
Number of events, n (%)393 (64.2%)454 (73.9%)
Median PFS (95% CI) (months)6.90 (6.51, 7.20)4.67 (4.21, 5.36)
Stratified Hazard ratio (95% CI)0.758 (0.661, 0.869)
Stratified Log-Rank test p-valueStratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no)0.00007
Overall Response Rate (ORR)
ORR (CR+PR) (95% CI)Overall objective response rate by IRC19.8% (16.4%, 23.2%)11.1% (8.5%, 13.8%)
Stratified Cochran-Mantel-Haenszel test p-value0.0001

Geriatric Use

8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9) ]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI.

Pediatric Use

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 months), there were similar effects. The skeletal and nasal cavity effects were not reversible after a post-dosing recovery period.

Pregnancy

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).

Use In Specific Populations

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 Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating ZALTRAP. Contraception 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) ] . Females Advise female patients of reproductive potential to use effective contraception during treatment with ZALTRAP and for 1 month 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 months), there were similar effects. The skeletal and nasal cavity effects were not reversible after a post-dosing recovery period. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9) ]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. 8.6 Renal Impairment No dosage modification is recommended for patients with renal impairment [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times upper limit normal [ULN] and any aspartate transaminase [AST]) and moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3) ] . ZALTRAP has not been studied in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

How Supplied

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.

Storage And Handling

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.

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