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ZALTRAP ziv-aflibercept 200 mg/8mL Solution, Concentrate — NDC 00024-5841-01 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

ZALTRAP ziv-aflibercept 200 mg/8mL Solution, Concentrate — NDC 0024-5841-01 (Billing 00024-5841-01)

by sanofi-aventis U.S. LLC · 1 VIAL in 1 CARTON / 8 mL in 1 VIAL

This is a package of ZALTRAP ziv-aflibercept 200 mg/8mL Solution, Concentrate from sanofi-aventis U.S. LLC, marketed since Aug 2012 and currently FDA-listed. It is this product's only package size.

NDC 00024-5841-01
🏷️ FDA NDC (as labeled) 0024-5841-01 billing pads the labeler segment with a zero
Rx only Brand On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 8, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 0024-5841-01 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
0024 labeler · 5841 product · 01 package
Package marketed since
Aug 3, 2012
Sample package
No — commercial package
Listing certified through
Dec 31, 2026
Barcode (UPC-A, from the NDC)
3 0024584101 8
FDA record last changed
Jul 24, 2026

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 0024-5841-01
Product NDC 0024-5841
11-digit billing NDC 00024584101
NCPDP billing unit ML — per mL (volume)
RxCUI 1723187, 1723189, 1723193, 1723194
UNII 15C2VL427D
Application # BLA125418
SPL Set ID f6725df6-50ee-4b0a-b900-d02ba634395d
Established class (EPC) Vascular Endothelial Growth Factor Inhibitor
Mechanism of action Vascular Endothelial Growth Factor Inhibitors
DEA schedule Non-controlled
Marketing category BLA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2012-08-03
Route INTRAVENOUS
Dosage form SOLUTION, CONCENTRATE
Substance AFLIBERCEPT
Biologic (Purple Book) 351(a)

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 21335010102030
GPI class Zaltrap
GCN Seq No 069781
GCN 32989
HICL code 040362
Ingredient (HICL) Ziv-Aflibercept
HIC1 code V
Therapeutic class — broad (HIC1) Neoplasms
HIC2 code V3
Therapeutic class — intermediate (HIC2) Antineoplastic Drugs (Continued 1)
HIC3 code V3N
Therapeutic class — specific (HIC3) Antineoplastic - Vegf-A,B And Plgf Inhibitors
AHFS code 10:00.00.00
AHFS class Antineoplastic Agents
FDB label name ZALTRAP 200 MG/8 ML VIAL
FDB brand name Zaltrap
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 069781
  • GCN: 32989
  • GPI-14 (Medi-Span): 21335010102030
  • HICL (First Databank): 040362
  • AHFS class code: 10:00.00.00
  • RxCUI (RxNorm): 1723187
Why two NDCs? The FDA registers this code as 0024-5841-01 — a 4-4-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the labeler segment → 00024-5841-01. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Vascular Endothelial Growth Factor Inhibitor class.

Pharmacologic class Vascular Endothelial Growth Factor Inhibitor
Drug family (ATC) Other antineoplastic agents, Antineovascularisation agents
How it works Vascular Endothelial Growth Factor Inhibitors
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name ZALTRAP 200 MG/8 ML VIAL Ingredient Ziv-Aflibercept
📖 What it is MedlinePlus · NLM

Aflibercept injection is used to treat: wet age-related macular degeneration (AMD; an ongoing disease of the eye that causes loss of the ability to see straight ahead and may make it more difficult to read, drive, or perform other daily activities) diabetic macular edema (an eye disease caused by diabetes that can lead to vision loss) diabetic retinopathy (damage to the eyes caused by diabetes) macular edema after retinal vein occlusion (an eye disease caused by blockage of blood flow from the eye that leads to blurry vision and vision loss) retinopathy of prematurity (ROP; an eye disea...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • Zaltrap is given with FOLFIRI chemotherapy to treat metastatic colorectal cancer. It is for cancer that has resisted or progressed after an oxaliplatin-containing treatment.
  • It is given as an IV infusion over about 1 hour, usually every 2 weeks, before the FOLFIRI drugs. It is never given as a quick push. Your care team will follow the label for your d...
  • Common ones include diarrhea, mouth sores, tiredness, low blood counts, high blood pressure, protein in the urine, nosebleeds, headache and decreased appetite. Tell your team about...
  • Call for serious bleeding, severe belly pain, chest pain, stroke-like symptoms, very high blood pressure, a severe headache with confusion, fever or infection signs, or severe diar...
📖 Read our full Ziv-aflibercept Injection guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer mLPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · quarterly No Part D plan price is available for this NDC in our data.
Medicare Part B allowsASP · J9400 $8.674 / J9400 unit —
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Billing & reimbursement

FDA NDC (as labeled)0024-5841-01
11-digit billing NDC00024-5841-01
Format4-4-2 as registered → padded to 5-4-2 for billing (zero added to the labeler segment)
HCPCS J-codeJ9400
DescriptorInjection, ziv-aflibercept, 1 mg
Billing units / pkg200 units
How the units are derivedThis package is 8; the HCPCS unit is 1 MG, so one package = 200 billing units.
Medicare Part B spend (2026 (Q1))$47,192 · 17 claims · $2,775.98 per claim (all NDCs under J9400)
Crosswalk sourceCMS ASP NDC-HCPCS Crosswalk
Where does this data come from?
The HCPCS J-code crosswalk comes from the CMS ASP NDC-HCPCS crosswalk and the DMEPDAC (DME MAC) NDC-HCPCS crosswalk — free public CMS data. Billing units are derived from the code’s descriptor and the package amount.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
00024-5841-01 You're viewing this Main listing 1 VIAL in 1 CARTON / 8 mL in 1 VIAL 2012-08-03 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Zaltrap 200 mg/8mLthis 00024-5841-01 sanofi-aventis 1 vial — — FDA listed —
About this product: this is a biologic. Biologics don't have small-molecule generics — competition comes from FDA-licensed biosimilars (shown above), not generics.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & biosimilar status

🏛️
2012
First FDA approval
Aug 2012
📍
2026
Currently FDA-listed
14 years listed
🔓
·
Biosimilar pathway open
listed protections lapsed 2024
🧬Biologic — competition comes from biosimilars

Biologics have no small-molecule generics; biosimilar competition is tracked in the FDA Purple Book.

🛡️ Latest patent/protection date listed: The latest listed FDA patent/protection lapsed Aug 2024 — those protections no longer apply, though a biosimilar still needs FDA licensure and a manufacturer to market it.
📅 FDA approved Aug 3, 2012

Why the date isn’t exact: Biosimilar timing can change because patents may be challenged, settled, licensed, added or removed, and litigation can move the real date earlier or later.

FDA Purple Book — biosimilars & interchangeables ⓘ
Reference product
ZaltrapZiv-Aflibercept
🔒 No FDA-licensed biosimilars or interchangeable biosimilars are listed yet for this biologic. It currently has no biosimilar competition in the FDA Purple Book.
Source: FDA Purple Book (purplebooksearch.fda.gov), matched on the reference product’s active ingredient.
Patents & exclusivity — FDA Purple Book
Exclusivity RefProduct
2012 2014 2016 2018 2020 2022 2024
Today
LOE
Biologic patent Exclusivity
🏛️Reference-product exclusivity
A flat 12 years of FDA market protection from first licensure. No biosimilar can be licensed before it ends — regardless of patents.
🧪Listed biologic patents
Patents the reference maker lists covering the molecule, formulation, or manufacturing. A biosimilar generally can’t launch until these resolve.
🔁Interchangeability
An interchangeable biosimilar may be substituted at the pharmacy (state laws vary). The first one can earn its own exclusivity period.
🛈 What do these terms mean?
Biologic patent
A patent the reference product’s maker has publicly listed. A biosimilar generally can’t launch until these expire — unless they’re invalidated or resolved in a settlement.
Reference-product exclusivity
A flat 12 years of FDA market protection from the biologic’s first licensure (the BPCIA). No biosimilar can be licensed before it ends, regardless of patents.
Interchangeable exclusivity
The first interchangeable biosimilar can earn a period as the only interchangeable version (pharmacists can substitute it without the prescriber).
Earliest biosimilar (LOE)
The latest of all the dates above — the soonest a biosimilar can realistically reach the market. Litigation and settlements can move it earlier.

Biologics have no small-molecule “generics” — competition comes from FDA-licensed biosimilars, tracked in the FDA Purple Book.

FDA exclusivity
CodeWhat it grantsExpires
RefProductReference-product exclusivity (12-year, BPCIA) — no biosimilar can be licensed before this dateAug 3, 2024
Common questions
Is there a biosimilar for ZALTRAP 200 MG/8 ML VIAL?
No FDA-licensed biosimilar is currently listed for this biologic in the FDA Purple Book.
Why do different websites show different biosimilar dates?
Biosimilar availability isn’t based on one single date. Some sources use the reference-product exclusivity, some use the last listed patent, and patent litigation, settlements, and licenses can all change the real-world launch date. This page shows the underlying Purple Book dates so you can see why estimates differ.
Can a biosimilar launch before the last patent expires?
Sometimes. A biosimilar maker may settle with the reference manufacturer or receive a license to launch earlier. In other cases, the last listed protection delays competition.
What does “current Purple Book estimate” mean?
It means we’re using the latest patent and exclusivity dates currently listed in the FDA Purple Book. It is not a guaranteed launch date.
What does “FDA listed” mean?
It means the product appears in the FDA’s official directory. That’s a good sign a product exists for the U.S. market, but on its own it does not confirm a pharmacy can get it today. Where we have recent retail pricing data, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Purple Book for a patent or exclusivity on the reference biologic. It can affect when a biosimilar becomes widely available — but it is not a guaranteed launch date. Settlements and licenses can move the real date earlier or later.
Built from the FDA Purple Book Patent List (patents the reference-product sponsor has publicly listed under the BPCIA) plus reference-product exclusivity. Biosimilars cannot launch until these clear; patent litigation and settlements can shift the real date. Biologics have no small-molecule generics — competition comes from FDA-licensed biosimilars, not the Orange Book.
Where does this data come from?
Patents and exclusivity from the FDA Purple Book (biologics), refreshed from public FDA data. Biosimilar launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

🧪 Avoiding an ingredient? See Ziv-aflibercept Injection inactive ingredients by manufacturer: every current product's list side by side, so you can ask your pharmacy for the version that does not list it.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII 2968PHW8QP
    A weak organic acid derived from citrus fruits or made through fermentation. It works as a buffer to control pH, a preservative to extend shelf life, and a flavoring agent in medications.
  • UNII QTT17582CB
    A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
  • UNII 7T1F30V5YH
    A synthetic emulsifier derived from sorbitol and oleic acid. It helps mix oil and water-based ingredients together and keeps them from separating in liquid formulations.
  • UNII 451W47IQ8X
    Sodium chloride is common table salt. It's used in medicines as a buffer to maintain proper pH, as a filler to add bulk, or to adjust the osmotic balance in liquid formulations.
  • UNII 55X04QC32I
    A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
  • UNII 70WT22SF4B
    A mineral salt that acts as a buffer to maintain the pH balance of the medication. It helps stabilize the drug's potency and prevents unwanted chemical changes during storage.
  • UNII 593YOG76RN
    A salt made from sodium and phosphate that helps regulate acidity and maintain proper pH balance in the medicine. It also acts as a buffer to keep the product stable.
  • UNII C151H8M554
    A natural sugar derived from sugar cane or sugar beets. It's used as a sweetener, filler, and binder to improve taste, add bulk, and help hold tablet or capsule ingredients together.
  • UNII B22547B95K
    A salt derived from citric acid that helps maintain the proper acid-base balance in the medicine. It's used as a buffer to keep the product stable and at the right pH level.
  • UNII 059QF0KO0R
    Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.

10 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

Labelersanofi-aventis U.S. LLC
FDA applicationBLA125418 (BLA)
Labeler code00024
First marketedAug 2012
Product typeHuman Prescription Drug
Portfolio85 products on file

More NDCs from sanofi-aventis U.S. LLC labeler code 00024

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📦 Storage and Handling 📋 Description 💬 Information for Patients 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Package Label / Principal Display Panel
🎯 Indications and Usage 73 words ▾

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 )

⏱️ Dosage and Administration ~2 min read ▾

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 )

2.1Recommended 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.

2.2Dosage 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) ] .

2.3Preparation 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

💊 Dosage Forms and Strengths 57 words ▾

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 )

⛔ Contraindications 7 words ▾

4 CONTRAINDICATIONS None. None ( 4 )

⚠️ Warnings and Cautions ~3 min read ▾

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 )

5.1Hemorrhage 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) ] .

5.2Gastrointestinal 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) ] .

5.3Impaired 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… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

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.

6.1Clinical 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

3.0Blood 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

0.5Proctalgia 5 0.3 2

0.3Investigations AST increased 62 3 54 2 ALT increased 50 3 39 2 Weight decreased 32 3 14

0.8Renal and urinary disorders Proteinuria Compilation of clinical and… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions 32 words ▾

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) ] .

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 )

8.1Pregnancy 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).

8.2Lactation 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.

8.3Females 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) ] .

8.4Pediatric 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… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy 210 words ▾

8.1Pregnancy 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).

🧒 Pediatric Use ~1 min read ▾

8.4Pediatric 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.

🧓 Geriatric Use 87 words ▾

8.5Geriatric 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.

🧬 Clinical Pharmacology ~2 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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 110 words ▾

12.1Mechanism 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.

📦 How Supplied / Storage and Handling 79 words ▾

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 28 words ▾

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.

📋 Description 162 words ▾

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.

💬 Information for Patients ~2 min read ▾

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 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 3 months 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) ] .

🧬 Pharmacokinetics ~1 min read ▾

12.3Pharmacokinetics 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.

🧬 Pharmacodynamics 85 words ▾

12.2Pharmacodynamics 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.

🔬 Clinical Studies ~2 min read ▾

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

🧪 Nonclinical Toxicology 182 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.

13.2Animal 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, Mutagenesis, Impairment of Fertility 142 words ▾

13.1Carcinogenesis, 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.

📄 Package Label / Principal Display Panel 110 words ▾

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

PRINCIPAL DISPLAY PANEL - 200 mg/8 mL Vial Carton NDC 0024-5841-01 ZALTRAP ® (ziv-aflibercept) Injection for Intravenous Infusion 200 mg/8 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 - 200 mg/8 mL Vial Carton

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for ZALTRAP (this brand).

Top reported reactions

Diarrhoea178
Hypertension137
Neutropenia105
Asthenia73
Vomiting68
Proteinuria64
Death61

Age at onset

Neonate1
Adult348
Elderly262

Reporter sex

0 reports
Male · 57%
Female · 40%
Unknown · 3%

Serious outcomes

Hospitalization591
Death207
Life-threatening67
Disabling19
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 184 0
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.

About this NDC listing & data coverage

Finished prescription product
What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos ✓ Available
Inactive ingredients (structured) ✓ Available
NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data ✓ Available
HCPCS J-code billing crosswalk ✓ Available
Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by sanofi-aventis U.S. LLC. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
sanofi-aventis U.S. LLC is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
Does this product have a billing J-code?
Yes — this NDC cross-references HCPCS code J9400 for medical-claim billing (typically used when a product is administered in a clinical setting rather than dispensed at a retail pharmacy). See the Billing section on this page.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 00024-5840-01 · sanofi-aventis 00024-5851-30 · Sanofi-Aventis →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.