Version July 2025
Dosage guidance
Safety: Withhold ziv-aflibercept 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.
Clinical considerations: Do not initiated ziv-aflibercept in patients with severe hemorrhage.
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 (Ref). 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 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
No dosage adjustment necessary.
Nephrotoxicity during treatment:
Proteinuria (≥2 g/24 hours): Temporarily withhold ziv-aflibercept until proteinuria <2 g/24 hours and then resume at previous dose.
Recurrent proteinuria: Temporarily withhold ziv-aflibercept until proteinuria <2 g/24 hours and then resume ziv-aflibercept with a permanent dose reduction to 2 mg/kg every 2 weeks.
Nephrotic syndrome or thrombotic microangiopathy: Discontinue ziv-aflibercept.
Mild (total bilirubin >1 to 1.5 times ULN and any AST) to moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment: No dosage adjustment necessary.
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).
Note: Other concomitant anticancer therapies may also require dosage adjustment.
Arterial thrombotic events: Discontinue ziv-aflibercept.
Fistula formation: Discontinue ziv-aflibercept.
GI perforation: Discontinue ziv-aflibercept.
Hemorrhage, severe: Discontinue ziv-aflibercept.
Hypertension: Manage with appropriate antihypertensive therapy (may require adjustment of existing antihypertensives). If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications (Ref). If ziv-aflibercept is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (Ref).
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 or delay ziv-aflibercept (and FOLFIRI) until ANC is ≥1500/mm3.
Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue ziv-aflibercept.
Wound healing impairment: Discontinue ziv-aflibercept.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reactions reported in combination therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI).
>10%:
Cardiovascular: Hypertension (41%)
Dermatologic: Palmar-plantar erythrodysesthesia (11%)
Endocrine & metabolic: Weight loss (32%)
Gastrointestinal: Abdominal pain (27%), decreased appetite (32%), diarrhea (69%, including severe diarrhea), stomatitis (50%; grades 3/4: 13%), upper abdominal pain (11%)
Genitourinary: Proteinuria (62%)
Hematologic & oncologic: Hemorrhage (38%; grades 3/4: 3%), leukopenia (78%; grades 3/4: 16%), neutropenia (67%; grades 3/4: 37%), thrombocytopenia (48%; grades 3/4: 3%)
Hepatic: Increased serum alanine aminotransferase (50%), increased serum aspartate aminotransferase (62%)
Immunologic: Antibody development (3%; neutralizing: 35%)
Infection: Infection (46%)
Nervous system: Fatigue (48%), headache (22%), voice disorder (25%)
Neuromuscular & skeletal: Asthenia (18%)
Renal: Increased serum creatinine (23%)
Respiratory: Dyspnea (12%), epistaxis (28%)
1% to 10%:
Cardiovascular: Arterial thromboembolism (3%), pulmonary embolism (5%), venous thromboembolism (9%, including deep vein thrombosis)
Dermatologic: Hyperpigmentation (8%)
Endocrine & metabolic: Dehydration (9%)
Gastrointestinal: Gastrointestinal hemorrhage (grades 3/4: ≤3%), hemorrhoids (6%), rectal pain (5%)
Genitourinary: Hematuria (grades 3/4: ≤3%), urinary tract infection (9%)
Hematologic & oncologic: Febrile neutropenia (grades 3/4: 4%), neutropenic infection (grades 3/4: ≤2%), postprocedural hemorrhage (grades 3/4: ≤3%), rectal hemorrhage (5%)
Infection: Neutropenic sepsis (grades 3/4: ≤2%)
Respiratory: Oropharyngeal pain (8%), rhinorrhea (6%)
Miscellaneous: Fistula (2%)
<1%:
Cardiovascular: Hypertensive crisis
Gastrointestinal: Gastrointestinal perforation
Genitourinary: Nephrotic syndrome
Hematologic & oncologic: Thrombotic microangiopathy
Hypersensitivity: Severe hypersensitivity reaction
Nervous system: Reversible posterior leukoencephalopathy syndrome
Miscellaneous: Wound healing impairment
Frequency not defined:
Cardiovascular: Angina pectoris, cerebrovascular accident
Gastrointestinal: Tooth infection
Hematologic & oncologic: Pulmonary hemorrhage
Local: Catheter infection
Nervous system: Intracranial hemorrhage
Respiratory: Hemoptysis, nasopharyngitis, pneumonia, upper respiratory tract infection
Postmarketing:
Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, cardiac failure, coronary artery dissection, myocardial rupture (arterial rupture and aortic rupture), reduced ejection fraction
Neuromuscular & skeletal: Osteonecrosis of the jaw
There are no contraindications listed in the manufacturer’s labeling.
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.
• 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 patients ≥65 years of age 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.
• GI perforation: GI perforation, including fatal GI perforation, may occur in patients receiving ziv-aflibercept.
• 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). 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. 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.
• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome have been reported. Symptoms generally resolve or improve within days following ziv-aflibercept discontinuation, although persistent neurologic symptoms and death have been reported.
• Thromboembolism: Arterial thrombotic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina, have occurred.
• Wound healing impairment: Severely impaired wound healing may occur in patients receiving ziv-aflibercept with FOLFIRI. The safety of resuming ziv-aflibercept treatment after resolution of wound healing complications has not been established.
Special populations:
• Older adult: Certain adverse events, such as diarrhea, dizziness, weakness, weight loss, and dehydration, occurred at a higher incidence in patients ≥65 year of age, compared to patients <65 years of age.
• Patients undergoing surgery or procedures: 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.
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)
No
Solution (Zaltrap Intravenous)
100 mg/4 mL (per mL): $480.00
200 mg/8 mL (per mL): $480.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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.
Ascites, symptomatic, due to malignant ovarian cancer
Ziv-aflibercept may be confused with aflibercept
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Androgens: Hypertension-Associated Agents may increase hypertensive effects of Androgens. Risk C: Monitor
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
BCG (Intravesical): Myelosuppressive Agents may decrease therapeutic effects of BCG (Intravesical). Myelosuppressive Agents may increase adverse/toxic effects of BCG (Intravesical). Risk X: Avoid
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may increase adverse/toxic effects of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Cladribine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk X: Avoid
CloZAPine: Myelosuppressive Agents may increase adverse/toxic effects of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor
Deferiprone: Myelosuppressive Agents may increase neutropenic effects 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. Risk D: Consider Therapy Modification
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider Therapy Modification
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Solriamfetol: May increase hypertensive effects of Hypertension-Associated Agents. Risk C: Monitor
Verify pregnancy status prior to use. Patients who could become pregnant should use effective contraception during therapy and for 3 months following the last ziv-aflibercept dose.
Ziv-aflibercept may impair reproductive function in patients of reproductive potential.
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).
It is not known if ziv-aflibercept is present in breast milk.
Aflibercept is present in breast milk following intravitreal administration (Juncal 2020).
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during ziv-aflibercept therapy and for 1 month following the last ziv-aflibercept dose.
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). Monitor BP (every 2 weeks; more frequently if clinically indicated; continue monitoring BP regularly following initiation of antihypertensive therapy). Verify pregnancy status prior to use in patients who could become pregnant. Monitor for signs/symptoms of bleeding/hemorrhage, fistula, and/or GI perforation. Monitor elderly patients closely for diarrhea and/or dehydration. Monitor for signs/symptoms of reversible posterior leukoencephalopathy syndrome (confirm diagnosis with MRI). Monitor wounds for healing impairment.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017], ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months during the first year and every 6 to 12 months thereafter for moderate-risk patients) (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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)
Body weight: Patients weighing ≥100 kg had a 29% increase in systemic exposure compared with patients weighing 50 to 100 kg.
