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Ziv-Aflibercept (Systemic)

Medically reviewed by Last updated on Jun 5, 2020.


(ziv a FLIB er sept)

Index Terms

  • Aflibercept IV
  • Vascular Endothelial Growth Factor Trap
  • VEGF Trap
  • VEGF Trap R1R2

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Zaltrap: 100 mg/4 mL (4 mL); 200 mg/8 mL (8 mL)

Brand Names: U.S.

  • Zaltrap

Pharmacologic Category

  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor
  • Vascular Endothelial Growth Factor (VEGF) Inhibitor


Ziv-aflibercept is a recombinant fusion protein which is comprised of portions of binding domains for vascular endothelial growth factor (VEGF) receptors 1 and 2, attached to the Fc portion of human IgG1. Ziv-aflibercept acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF) which prevent VEGF receptor binding/activation to their receptors (an action critical to angiogenesis), thus leading to antiangiogenesis and tumor regression.

Half-Life Elimination

~6 days (range: 4 to 7 days)

Special Populations Note

Body weight: Patients weighing ≥100 kg had a 29% increase in systemic exposure compared with patients weighing 50 to 100 kg.

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]) that is resistant to or has progressed on an oxaliplatin-based regimen.

Off Label Uses

Ascites (symptomatic; due to malignant ovarian cancer)

Data from a multicenter, double-blind, placebo-controlled, parallel group, phase 2 trial in patients with advanced chemoresistant ovarian cancer (including fallopian tube or primary peritoneal adenocarcinoma) and recurrent symptomatic malignant ascites (requiring paracenteses) suggest that ziv-aflibercept may be efficacious in managing refractory ascites and providing symptomatic relief, although vascular endothelial growth factor (VEGF) blockade should be used with caution in this patient population due to the risk of fatal GI perforation (Gotlieb 2012).


There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Ascites, symptomatic; due to malignant ovarian cancer (off-label use; based on limited data): IV: 4 mg/kg every 2 weeks for 2 to 6 months (Gotlieb 2012). Note: Vascular endothelial growth factor (VEGF) blockade should be used with caution in this patient population due to the risk of fatal GI perforation.

Colorectal cancer, metastatic: IV: 4 mg/kg (based on actual body weight) every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]), continue until disease progression or unacceptable toxicity (Van Cutsem 2012).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Arterial thrombotic events: Discontinue ziv-aflibercept treatment.

Fistula formation: Discontinue ziv-aflibercept treatment.

Gastrointestinal perforation: Discontinue ziv-aflibercept treatment.

Hemorrhage, severe: Discontinue ziv-aflibercept treatment.


Uncontrolled hypertension: Temporarily withhold ziv-aflibercept treatment until controlled and then resume with a permanent dose reduction to 2 mg/kg every 2 weeks.

Hypertensive crisis or hypertensive encephalopathy: Discontinue ziv-aflibercept treatment.

Neutropenia: Temporarily withhold ziv-aflibercept (and FOLFIRI) treatment until ANC is ≥1500/mm3.

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue ziv-aflibercept treatment.

Surgery/wound healing impairment:

Elective surgery: Temporarily withhold ziv-aflibercept treatment for at least 4 weeks prior to elective surgery; do not resume until at least 4 weeks after major surgery AND until wound is fully healed; for minor surgery (eg, biopsy, central venous port placement, tooth extraction), may be resumed after wound is fully healed.

Wound healing impaired: Discontinue ziv-aflibercept treatment.

Note: For toxicities related to FOLFIRI, refer to individual Fluorouracil or Irinotecan monographs.


Prior to infusion, dilute in D5W or NS to a final concentration of 0.6 to 8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing DEHP or polyolefin infusion bags. After initial vial puncture, do not re-enter vial. Do not mix with other medications.


IV: Infuse over 1 hour. Do not administer as an IV push or bolus. Administer prior to any FOLFIRI component. Do not administer other medications through the same intravenous line.

Infuse via a 0.2 micron polyethersulfone filter; do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Administer with one of the following types of infusion sets: Polyvinyl chloride (PVC) containing DEHP, DEHP-free PVC containing trioctyl-trimellitate (TOTM), polypropylene, polyethylene lined PVC, or polyurethane.


Store intact vials at 2°C to 8°C (36°F to 46°F). Protect from light (store in original outer carton).

Solutions diluted for infusion in D5W or NS may be stored in refrigerator for up to 24 hours, or at 20°C to 25°C (68°F to 77°F) for up to 8 hours.

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

Adverse Reactions

Note: Reactions reported in combination therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI).


Cardiovascular: Hypertension (41%)

Dermatologic: Palmar-plantar erythrodysesthesia (11%)

Endocrine & metabolic: Weight loss (32%)

Gastrointestinal: Diarrhea (69%), stomatitis (50%; grades 3/4: 13%), decreased appetite (32%), abdominal pain (27%), severe diarrhea (19%), upper abdominal pain (11%)

Genitourinary: Proteinuria (62%)

Hematologic & oncologic: Leukopenia (78%; grades 3/4: 16%), neutropenia (67%; grades 3/4: 37%), thrombocytopenia (48%; grades 3/4: 3%), hemorrhage (38%; grades 3/4: 3%)

Hepatic: Increased serum aspartate aminotransferase (62%), increased serum alanine aminotransferase (50%)

Immunologic: Antibody development (3%; neutralizing: 35%)

Infection: Infection (46%)

Nervous system: Fatigue (48%), voice disorder (25%), headache (22%)

Neuromuscular & skeletal: Asthenia (18%)

Renal: Increased serum creatinine (23%)

Respiratory: Epistaxis (28%), dyspnea (12%)

1% to 10%:

Cardiovascular: Venous thromboembolism (9%), pulmonary embolism (5%), arterial thromboembolism (3%)

Dermatologic: Hyperpigmentation (8%)

Endocrine & metabolic: Dehydration (9%)

Gastrointestinal: Hemorrhoids (6%), rectal hemorrhage (5%), rectal pain (5%), gastrointestinal hemorrhage (grades 3/4: ≤3%)

Genitourinary: Urinary tract infection (9%), hematuria (grades 3/4: ≤3%)

Hematologic & oncologic: Febrile neutropenia (grades 3/4: 4%), postprocedural hemorrhage (grades 3/4: ≤3%)

Infection: Neutropenic sepsis (grades 3/4: 2%)

Respiratory: Oropharyngeal pain (8%), rhinorrhea (6%)

Miscellaneous: Fistula formation (2%)

Frequency not defined:

Cardiovascular: Angina pectoris, cerebrovascular accident, deep vein thrombosis, transient ischemic attacks

Gastrointestinal: Tooth infection

Hematologic & oncologic: Pulmonary hemorrhage

Local: Catheter infection

Nervous system: Intracranial hemorrhage

Respiratory: Hemoptysis, nasopharyngitis, pneumonia, upper respiratory tract infection

<1%, postmarketing, and/or case reports: Cardiac failure, gastrointestinal perforation, nephrotic syndrome, osteonecrosis of the jaw, reduced ejection fraction, reversible posterior leukoencephalopathy syndrome, thrombotic microangiopathy, wound healing impairment


Concerns related to adverse effects:

• Bone marrow suppression: A higher incidence of neutropenia and complications due to neutropenia (neutropenic fever and infection), including grade 3 and 4 events, occurred with ziv-aflibercept. Leukopenia and thrombocytopenia have also occurred. Monitor CBC with differential (baseline and prior to each cycle); delay treatment until ANC is ≥1,500/mm3.

• Diarrhea: Severe diarrhea and dehydration (grades 3 and 4) have been reported with ziv-aflibercept. The incidence of diarrhea is increased in patients ≥65 years of age; monitor elderly patients closely for diarrhea.

• Fistula formation: The risk for GI and non-GI fistulas is increased with ziv-aflibercept. Fistula sites have included anal, enterovesical, enterocutaneous, colovaginal, and intestinal. Discontinue ziv-aflibercept in patients who develop fistula.

• GI perforation: GI perforation, including fatal GI perforation, may occur in patients receiving ziv-aflibercept. Discontinue ziv-aflibercept therapy in patients who experience GI perforation. Monitor for signs/symptoms of GI perforation.

• Hemorrhage: The risk for hemorrhage is increased with ziv-aflibercept. Severe and sometimes fatal hemorrhage, including GI bleeding, has been reported in patients who have received ziv-aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI). Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ziv-aflibercept to patients with severe hemorrhage. Discontinue if severe hemorrhage develops. Grade 3 and 4 hemorrhagic events, including hematuria and postprocedural hemorrhage, have been reported. Intracranial hemorrhage and pulmonary hemorrhage/hemoptysis (including fatal events) have also occurred.

• Hypertension: The risk for grades 3 or 4 hypertension is increased with ziv-aflibercept. Onset is generally within the first 2 treatment cycles. Monitor blood pressure every 2 weeks (more frequently if clinically indicated). Manage with appropriate antihypertensive therapy (may require adjustment of existing antihypertensives). Temporarily withhold ziv-aflibercept treatment with uncontrolled hypertension; may reinitiate with permanent dose reduction when controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. Patients with NYHA class III or IV heart failure were excluded from clinical trials.

• Proteinuria/nephrotic syndrome: Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been associated with ziv-aflibercept. Evaluate for proteinuria during treatment with urine dipstick and/or urinary protein creatinine ratio (UPCR); if dipstick ≥2+ for protein or UPCR >1, obtain 24-hour urine collection. Withhold ziv-aflibercept for proteinuria ≥2 g per 24 hours; for recurrent proteinuria, withhold treatment until <2 g per 24 hours and then resume with permanent dose reduction. Discontinue treatment for nephrotic syndrome or TMA.

• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome have been reported. Confirm diagnosis with MRI; discontinue ziv-aflibercept if verified. Symptoms generally resolve or improve within days, although persistent neurologic symptoms and death have been reported

• Thromboembolism: Arterial thrombotic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina, have occurred. Discontinue ziv-aflibercept in patients who experience ATEs.

• Wound healing impairment: Severely compromised wound healing may occur in patients receiving ziv-aflibercept with FOLFIRI. Discontinue ziv-aflibercept in patients with compromised wound healing. Suspend ziv-aflibercept for at least 4 weeks prior to elective surgery, and do not resume ziv-aflibercept for at least 4 weeks after major surgery AND until the surgical wound is completely healed. For minor surgeries (eg, central venous access port placement, biopsy, tooth extraction), ziv-aflibercept may be resumed or initiated as soon as the surgical wound is fully healed. The safety of resuming ziv-aflibercept treatment after resolution of wound healing complications has not been established.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Certain adverse events, such as diarrhea, dizziness, weakness, weight loss, and dehydration, occurred at a higher incidence in elderly patients compared to younger adults; monitor closely during treatment.

Monitoring Parameters

CBC with differential (baseline and prior to each cycle); urine protein (dipstick analysis and/or urinary protein creatinine ratio [UPCR], obtain 24-hour urine collection if dipstick ≥2+ for protein or UPCR >1); blood pressure (every 2 weeks; more frequently if clinically indicated). Evaluate pregnancy status prior to use in females of reproductive potential. Monitor for signs/symptoms of hemorrhage or GI perforation; monitor elderly patients closely for diarrhea and/or dehydration. Monitor wounds for healing impairment.

Reproductive Considerations

Verify pregnancy status in females of reproductive potential prior to initiating ziv-aflibercept. Females of reproductive potential should use effective contraception during therapy and for 1 month following the last ziv-aflibercept dose. Ziv-aflibercept may impair reproductive function in males and females of reproductive potential.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to ziv-aflibercept may cause fetal harm. Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor; VEGF is required to achieve and maintain normal pregnancies (Peracha 2016).

Patient Education

What is this drug used for?

• It is used to treat colorectal cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Weight loss

• Abdominal pain

• Diarrhea

• Lack of appetite

• Loss of strength and energy

• Mouth sores

• Mouth irritation

• Change in voice

• Skin discoloration

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes

• Swelling, warmth, numbness, change of color, or pain in a leg or arm

• Severe headache

• Severe dizziness

• Passing out

• Wound healing impairment

• Chest pain

• Shortness of breath

• Vision changes

• Redness or irritation of palms or soles of feet

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.