Ziv-aflibercept, a recombinant humanized fusion protein, is a vascular endothelial growth factor A (VEGF-A), VEGF-B, and placental growth factor (PlGF) antagonist that is used as an antineoplastic agent.1
The IV preparation of Zaltrap® (ziv-aflibercept) for use in the treatment of metatastic colorectal cancer contains the same drug as the intravitreal preparation of Eylea® (aflibercept), which is used in the treatment of macular degeneration.9, 10, 12 Because of the potential for medication errors, the US Food and Drug Administration (FDA) required the addition of a prefix to the nonproprietary (generic) name; FDA later approved the addition of the prefix “ziv” to the generic name of Zaltrap® (ziv-aflibercept) for the US market.10, 11
Ziv-aflibercept is used in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer that is refractory to or has progressed following oxaliplatin-based chemotherapy.1
The current indication for ziv-aflibercept in combination with FOLFIRI is based principally on the results of a randomized, double-blind, placebo-controlled, multinational phase 3 study (VELOUR) in adult patients with metastatic colorectal cancer whose disease was refractory to or had progressed during or within 6 months of oxaliplatin-based chemotherapy (with or without bevacizumab).1, 2, 8 In this study, 1226 patients were randomized in a 1:1 ratio to receive either ziv-aflibercept (4 mg/kg by IV infusion over 1 hour) in combination with FOLFIRI (irinotecan 180 mg/m2 by IV infusion over 90 minutes with leucovorin 400 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by rapid IV injection [“bolus”], and then fluorouracil 2400 mg/m2 by IV infusion over 46 hours) or placebo in combination with FOLFIRI.1, 2 Treatment was repeated every 2 weeks and continued until disease progression or unacceptable toxicity occurred.1, 2 The primary efficacy end point was overall survival.1, 2 The median age of patients enrolled in the study was 61 years (range: 19-86 years).1, 2 The majority (89-90%) of enrolled patients had received prior oxaliplatin-based chemotherapy for metastatic disease; 28% of patients had received bevacizumab in combination with prior oxaliplatin-based chemotherapy.1 The median duration of treatment was approximately 21 weeks for patients receiving ziv-aflibercept in combination with FOLFIRI (median of 7 cycles of ziv-aflibercept, 9 cycles overall) and approximately 18 weeks for patients receiving placebo in combination with FOLFIRI (8 cycles overall).2
Analysis of data at a median follow-up of 22.3 months indicated that patients receiving ziv-aflibercept in combination with FOLFIRI had a longer median overall survival compared with those receiving placebo in combination with FOLFIRI (13.5 versus 12.1 months, respectively).1, 2 The 2-year survival rate was 28% in patients receiving ziv-aflibercept in combination with FOLFIRI compared with 18.7% in those receiving placebo in combination with FOLFIRI.2 Treatment effects of ziv-aflibercept were consistent across various patient subgroups defined by age, gender, race, geographic region, number of organs with metastasis, liver metastasis, history of hypertension, and prior bevacizumab use.2, 8 Although not statistically significant (and there were fewer patients in the bevacizumab subgroup), patients who previously received bevacizumab appeared to benefit less from ziv-aflibercept treatment;8 the hazard ratio for overall survival was 0.86 in patients who received prior bevacizumab and 0.79 in those without prior bevacizumab exposure.1 Patients randomized to receive ziv-aflibercept in combination with FOLFIRI had a longer median progression-free survival compared with those receiving placebo in combination with FOLFIRI (6.9 versus 4.7 months, respectively).1, 2 In addition, patients receiving ziv-aflibercept in combination with FOLFIRI had a higher overall response rate compared with those receiving placebo in combination with FOLFIRI (19.8 versus 11.1%, respectively).1, 2
Ziv-aflibercept therapy should not be initiated in patients who have undergone surgery until after the surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Warnings/Precautions: Warnings, in Cautions.)
Clinicians should consult the respective manufacturers' labelings or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.1
Ziv-aflibercept is administered by IV infusion over 1 hour.1 The drug should not be administered by rapid IV injection, such as IV push or bolus. 1
Ziv-aflibercept injection must be diluted prior to administration.1 Prior to dilution, ziv-aflibercept injection should be inspected visually for particulate matter and discoloration; if particulate matter or discoloration is evident, the solution should not be used.1 Ziv-aflibercept is diluted by adding the appropriate dose (4 mg/kg) of ziv-aflibercept injection concentrate (containing 25 mg/mL) to a diethylhexyl phthalate (DEHP) plasticized polyvinylchloride (PVC) or non-PVC polyolefin infusion bag containing the appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield a final concentration of 0.6-8 mg/mL.1 No other drug should be added to or administered in the same IV line with ziv-aflibercept infusion.1
After dilution, ziv-aflibercept infusion solution should be administered by IV infusion through a 0.2-µm polyethersulfone filter; filters made of polyvinylidene fluoride (PVDF) or nylon should not be used.1 The diluted infusion solution should be administered through DEHP PVC, non-DEHP trioctyltrimellitate (TOTM) PVC, polypropylene, polyethylene-lined PVC, or polyurethane administration sets.1
Any unused portion left in the vial or infusion bag should be discarded since ziv-aflibercept injection contains no preservative.1
Diluted ziv-aflibercept infusion solution may be stored at 2-8°C for up to 4 hours.1 Unopened vials of ziv-aflibercept injection should be protected from light and stored in the original carton at 2-8°C.1
For the treatment of metastatic colorectal cancer that is refractory to or has progressed following oxaliplatin-based chemotherapy, the recommended dosage of ziv-aflibercept is 4 mg/kg by IV infusion over 1 hour in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI; irinotecan 180 mg/m2 by IV infusion over 90 minutes with leucovorin 400 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by rapid IV injection [“bolus], and then fluorouracil 2400 mg/m2 by IV infusion over 46 hours).1 Ziv-aflibercept should be administered prior to the FOLFIRI regimen on the day of treatment.1 The ziv-aflibercept-FOLFIRI combination regimen should be repeated every 2 weeks and continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If toxicities occur, temporary or permanent discontinuance of ziv-aflibercept may be required based on causality.1
Ziv-aflibercept should be discontinued in patients who develop severe hemorrhage, GI perforation, compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, or reversible posterior leukoencephalopathy syndrome (RPLS).1 (See Cautions: Warnings/Precautions.)
Ziv-aflibercept therapy should be temporarily suspended at least 4 weeks prior to elective surgery.1 Therapy also should be temporarily interrupted in patients who develop recurrent or severe hypertension or proteinuria.1 (See Hypertension and also Proteinuria under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Ziv-aflibercept therapy should be delayed in patients with a neutrophil count of less than 1500/mm3.1 (See Neutropenia and Neutropenic Complications under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If recurrent or severe hypertension occurs, ziv-aflibercept therapy should be interrupted until hypertension is controlled; therapy may then be resumed at a permanently reduced dosage of 2 mg/kg.1 If hypertensive crisis or hypertensive encephalopathy occurs, treatment with ziv-aflibercept should be discontinued.1 (See Hypertension under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Ziv-aflibercept therapy should be interrupted for proteinuria of or exceeding 2 g per 24 hours and resumed when proteinuria declines below this level.1 If proteinuria recurs, therapy should be withheld again until proteinuria declines below 2 g per 24 hours; therapy may then be resumed at a permanently reduced dosage of 2 mg/kg.1 If nephrotic syndrome or thrombotic microangiopathy occurs, treatment with ziv-aflibercept should be discontinued.1 (See Proteinuria under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
No dosage adjustment is required in geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for patients with hepatic or renal impairment.1 (See Hepatic Impairment and also Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states there are no known contraindications to the use of ziv-aflibercept.1
Ziv-aflibercept is associated with an increased risk of hemorrhage, including severe and sometimes fatal hemorrhage.1 In the VELOUR study, bleeding or hemorrhage (all grades) was reported in 38% of patients receiving ziv-aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with 19% of those receiving placebo in combination with FOLFIRI.1, 2 Grade 3 or 4 hemorrhagic events (including GI hemorrhage, hematuria, and postprocedural hemorrhage) were reported in 3% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 1% of those receiving placebo in combination with FOLFIRI.1 Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis, including fatal cases, have been reported in patients receiving ziv-aflibercept.1
Patients should be monitored for signs and symptoms of bleeding.1 Ziv-aflibercept should not be initiated in patients with severe hemorrhage.1 Ziv-aflibercept should be discontinued if severe hemorrhage occurs during therapy with the drug.1
GI perforation, sometimes fatal, has been reported in patients receiving ziv-aflibercept.1 In phase 3 studies in patients with various cancers (i.e., colorectal, pancreatic, and lung cancer), GI perforation (all grades) was reported in 0.8% of patients receiving ziv-aflibercept compared with 0.3% of those receiving placebo; grade 3 or 4 GI perforation was reported in 0.8 or 0.2% of patients receiving ziv-aflibercept or placebo, respectively.1
Patients should be monitored for signs and symptoms of GI perforation.1 Ziv-aflibercept should be discontinued if GI perforation occurs.1
Surgery and Wound Healing Complications
Grade 3 compromised wound healing has been reported in 0.3% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with none of those receiving placebo in combination with FOLFIRI.1
Ziv-aflibercept therapy should be suspended at least 4 weeks prior to elective surgery.1 The drug should not be resumed until at least 4 weeks following major surgery and after the surgical incision has fully healed.1 In patients undergoing minor surgery (e.g., central venous access port placement, biopsy, tooth extraction), ziv-aflibercept may be initiated or resumed after the surgical incision has fully healed.1
Ziv-aflibercept should be discontinued in patients with compromised wound healing.1
Other Warnings and Precautions
Fistula formation involving GI and non-GI sites has been reported in more patients receiving ziv-aflibercept compared with those receiving placebo.1 Fistula formation involving anal, enterovesical, enterocutaneous, colovaginal, and intestinal sites was reported in 1.5% of patients with metastatic colorectal cancer receiving ziv-aflibercept in combination with FOLFIRI compared with 0.5% of those receiving placebo in combination with FOLFIRI.1, 2 Grade 3 GI fistula formation was reported in 0.3% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 0.2% of those receiving placebo in combination with FOLFIRI.1, 2
Ziv-aflibercept should be discontinued if fistula formation occurs.1
Ziv-aflibercept is associated with an increased risk of grade 3 or 4 hypertension.1 In the VELOUR study, grade 3 hypertension (defined as requiring adjustment to existing antihypertensive therapy or treatment with more than one drug) was reported in 19% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 1.5% of those receiving placebo in combination with FOLFIRI.1, 2 Grade 4 hypertension (hypertensive crisis) was reported in 0.2% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with none of those receiving placebo in combination with FOLFIRI.1, 2 Among patients experiencing grade 3 or 4 hypertension, 54% developed hypertension during the first 2 cycles of therapy.1 In a phase 1 study evaluating ziv-aflibercept over a dosage range of 0.3-7 mg/kg every 2 weeks, the median time to onset of hypertension was 3.5 days; hypertension was reversible or manageable following discontinuance of ziv-aflibercept or initiation of appropriate supportive measures.7
Blood pressure should be monitored every 2 weeks or more frequently as clinically indicated during ziv-aflibercept therapy.1 If hypertension occurs, patients should be treated with appropriate antihypertensive therapy, and blood pressure should be monitored regularly.1 If hypertension recurs or becomes severe, temporary interruption of ziv-aflibercept therapy and subsequent dosage reduction is required.1 (See Hypertension under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Ziv-aflibercept should be discontinued in patients who develop hypertensive crisis or hypertensive encephalopathy.1
Ziv-aflibercept has not been evaluated in patients with New York Heart Association (NYHA) class III or IV heart failure.1
Arterial Thromboembolic Events
Arterial thromboembolic events (including transient ischemic attacks, cerebrovascular accident, and angina pectoris) have been reported in more patients with metastatic colorectal cancer receiving ziv-aflibercept in combination with FOLFIRI compared with those receiving placebo in combination with FOLFIRI (2.6 versus 1.7%, respectively).1 Grade 3 or 4 arterial thromboembolic events were reported in 1.8% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 0.7% of those receiving placebo in combination with FOLFIRI.1
Ziv-aflibercept should be discontinued in patients who experience an arterial thromboembolic event.1
Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy have been reported in more patients receiving ziv-aflibercept compared with those receiving placebo.1 In the VELOUR study, proteinuria occurred in 62% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 41% of those receiving placebo in combination with FOLFIRI.1, 2 Grade 3 or 4 proteinuria was reported in 8% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 1% of those receiving placebo in combination with FOLFIRI.1, 2 Nephrotic syndrome occurred in 0.5% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with none of those receiving placebo in combination with FOLFIRI.1 Thrombotic microangiopathy has been reported in 3 of 2258 patients with cancer receiving ziv-aflibercept in various studies.1 In a phase 1 study evaluating ziv-aflibercept over a dosage range of 0.3-7 mg/kg every 2 weeks, the median time to onset of proteinuria was 15 days; proteinuria was reversible or manageable following discontinuance of ziv-aflibercept or initiation of appropriate supportive measures.7
Urine dipstick and urinary protein to creatinine ratio should be monitored for the development or worsening of proteinuria during therapy.1 Patients with a urinary protein to creatinine ratio exceeding 1 should undergo further assessment with a 24-hour urine collection.1 Ziv-aflibercept therapy should be interrupted for proteinuria of or exceeding 2 g per 24 hours and resumed when proteinuria declines below this level.1 If proteinuria recurs, temporary interruption of ziv-aflibercept therapy and subsequent dosage reduction is required.1 (See Proteinuria under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Ziv-aflibercept should be discontinued in patients who develop nephrotic syndrome or thrombotic microangiopathy.1
Neutropenia and Neutropenic Complications
Neutropenic complications (e.g., febrile neutropenia, neutropenic infection) have been reported in more patients receiving ziv-aflibercept compared with those receiving placebo.1 Grade 3 or 4 neutropenia occurred in 37% of patients with metastatic colorectal cancer receiving ziv-aflibercept in combination with FOLFIRI compared with 30% of those receiving placebo in combination with FOLFIRI.1, 2 Grade 3 or 4 febrile neutropenia or neutropenic infection/sepsis was reported in 4 or 1.5%, respectively, of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 2 or 1.2%, respectively, of those receiving placebo in combination with FOLFIRI.1
Complete blood cell (CBC) counts, including differential, should be monitored at baseline and prior to initiation of each cycle of ziv-aflibercept.1 Therapy with ziv-aflibercept should be delayed until neutrophil counts are at least 1500/mm3.1
Grade 3 or 4 diarrhea has been reported in more patients receiving ziv-aflibercept in combination with FOLFIRI compared with those receiving placebo in combination with FOLFIRI (19 versus 8%, respectively).1 Grade 3 or 4 dehydration has been reported in 4% of patients receiving ziv-aflibercept in combination with FOLFIRI compared with 1% of those receiving placebo in combination with FOLFIRI.1 Diarrhea is more likely to occur in patients 65 years of age or older.1
Patients 65 years of age or older should be monitored more closely for diarrhea and dehydration.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in 0.5% of patients receiving ziv-aflibercept alone or in combination with chemotherapy.1
If signs or symptoms of RPLS develop, diagnosis of RPLS should be confirmed by magnetic resonance imaging (MRI), and ziv-aflibercept therapy should be discontinued.1 Symptoms of RPLS usually resolve or improve within days, but some patients have experienced ongoing neurologic sequelae or death.1
As with all therapeutic proteins, there is a potential for immunogenicity.1, 3 In multiple studies in patients who received ziv-aflibercept for various malignancies, anti-product antibody formation occurred in 3.1% of patients receiving ziv-aflibercept compared with 1.7% of those receiving placebo.1 Among those patients who tested positive for anti-product antibodies, neutralizing antibodies were detected in 17 of 48 patients (35%) receiving ziv-aflibercept and in 2 of 40 patients (5%) receiving placebo.1 Mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population; the clinical relevance of neutralizing antibodies is not known.1
Because the observed incidence of antibody positivity may be influenced by several factors including sample handling, timing of sample collection, concomitant drug therapy, and underlying disease, comparison of the incidence of antibodies to ziv-aflibercept to that of other drugs may be misleading.1
Category C.1 (See Users Guide.) (See Advice to Patients.)
It is not known whether ziv-aflibercept is distributed into milk in humans.1 Because of the potential for serious adverse reactions to ziv-aflibercept in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of ziv-aflibercept have not been established in pediatric patients younger than 18 years of age.1, 2, 8
In the VELOUR study, 34% of patients were 65 years of age or older and 5% were 75 years of age or older.1 Although no overall differences in efficacy (i.e., overall survival) were observed between geriatric and younger patients, the incidences of diarrhea, dizziness, asthenia, weight loss, and dehydration were higher among patients 65 years of age or older compared with younger patients.1 Geriatric patients should be monitored more closely for diarrhea and dehydration.1 (See Diarrhea and Dehydration under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Dosage adjustment is not required in patients 65 years of age or older.1
The effects of hepatic impairment on the pharmacokinetics of ziv-aflibercept have not been formally studied.1 Analysis of population pharmacokinetic data from 1507 patients indicates that ziv-aflibercept exposure and clearance are similar between patients with mild (total bilirubin concentration exceeding 1-1.5 times the upper limit of normal [ULN] and any AST concentration) or moderate (total bilirubin concentration exceeding 1.5-3 times the ULN and any AST concentration) hepatic impairment and those with normal hepatic function.1 Data are not available for patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN and any AST concentration).1
The effects of renal impairment on the pharmacokinetics of ziv-aflibercept have not been formally studied.1 Analysis of population pharmacokinetic data indicates that ziv-aflibercept exposure and clearance are similar between patients with mild (creatinine clearance of 50-80 mL/minute), moderate (creatinine clearance of 30-50 mL/minute), or severe (creatinine clearance less than 30 mL/minute) renal impairment and those with normal renal function.1
The most common adverse effects reported in 20% or more of patients receiving ziv-aflibercept in combination with FOLFIRI and at an incidence that is at least 2% higher than that reported with placebo in combination with FOLFIRI include leukopenia,1 diarrhea,1, 2 neutropenia,1 proteinuria,1 elevated aminotransferase (i.e., AST, ALT) concentrations,1 stomatitis,1, 2 fatigue,1 thrombocytopenia,1 hypertension,1, 2 weight loss,1 decreased appetite,1, 2 epistaxis,1, 2 abdominal pain,1, 2 dysphonia,1, 2 elevated serum creatinine concentration,1 and headache.1, 2
The most common grade 3 or 4 adverse effects reported in 5% or more of patients receiving ziv-aflibercept in combination with FOLFIRI and at an incidence that is at least 2% higher than that reported with placebo in combination with FOLFIRI include neutropenia,1 diarrhea,1 hypertension,1 leukopenia,1 stomatitis,1 fatigue,1 proteinuria,1 and asthenia.1
No formal drug interaction studies have been performed to date.1
Cross-study comparisons and population pharmacokinetic analyses indicate no clinically important pharmacokinetic interactions between ziv-aflibercept and irinotecan or between ziv-aflibercept and fluorouracil.1
Ziv-aflibercept, a recombinant humanized fusion protein, is a vascular endothelial growth factor A (VEGF-A), VEGF-B, and placental growth factor (PlGF) antagonist.1, 3 The drug consists of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2), fused to the Fc portion of human immunoglobulin G1 (IgG1).1, 2, 3 The IV preparation of Zaltrap® (ziv-aflibercept) for use in the treatment of metatastic colorectal cancer contains the same drug as the intravitreal preparation of Eylea® (aflibercept), which is used in the treatment of macular degeneration.9, 10, 12 Because of the potential for medication errors, the US Food and Drug Administration (FDA) required the addition of a prefix to the nonproprietary (generic) name; FDA later approved the addition of the prefix “ziv” to the generic name of Zaltrap® (ziv-aflibercept) for the US market.10, 11
Ziv-aflibercept acts as a soluble decoy receptor that binds to VEGF-A, VEGF-B, and PlGF and inhibits their biologic activity.2, 4 VEGF-A, VEGF-B, and PlGF are angiogenic factors that promote endothelial cell proliferation, survival, migration, and vascular permeability.4, 5 Binding of ziv-aflibercept to VEGF-A, VEGF-B, and PlGF prevents these factors from binding to their endogenous receptors, reducing neovascularization and vascular permeability.1 The binding affinity of ziv-aflibercept for VEGF-A isoforms is higher than that of bevacizumab; ziv-aflibercept also is more potent than bevacizumab in inhibiting VEGF-1 and VEGFR-2 activation.4 Ziv-aflibercept has been shown to inhibit angiogenesis by inhibiting proliferation of endothelial cells in animals; the drug also has been shown to inhibit the growth of xenotransplanted colon tumors in mice.1
Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics over a dosage range of 2-9 mg/kg.1, 7 Steady-state concentrations of free ziv-aflibercept are reached by the second dose.1 Following administration of ziv-aflibercept at a dosage of 4 mg/kg every 2 weeks, the accumulation ratio for free ziv-aflibercept is approximately 1.2; the elimination half-life of free ziv-aflibercept is approximately 6 days (range: 4-7 days).1
Analysis of population pharmacokinetic data indicates that age, race, and gender have no clinically important effects on exposure to free ziv-aflibercept.1 However, a 29% increase in systemic exposure to the drug has been observed in patients weighing 100 kg or more compared with those weighing 50-100 kg.1
Increased risk of severe bleeding.1 Importance of informing clinician of any episodes or symptoms of bleeding (e.g., lightheadedness).1
Risk of wound healing complications.1 Importance of discussing with clinician prior to undergoing any surgery or procedures (including tooth extractions).1
Risk of development or exacerbation of hypertension.1 Importance of receiving routine monitoring of blood pressure and informing clinician if blood pressure is elevated or if manifestations of hypertension (e.g., severe headache, lightheadedness, neurologic symptoms) occur.1
Importance of informing clinician of severe diarrhea, vomiting, or severe abdominal pain.1
Importance of informing clinician of fever or other signs and symptoms of infection.1
Risk of arterial thromboembolic events.1
Risk of fetal or neonatal toxicity.1 Necessity of advising women and men receiving ziv-aflibercept to use an effective method of contraception during and for at least 3 months after the last dose of ziv-aflibercept.1 Importance of immediately informing clinician if the patient or their partner becomes pregnant during therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 25 mg/mL (100 and 200 mg) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Sanofi-Aventis US, LLC. Zaltrap® (ziv-aflibercept) injection for intravenous infusion prescribing information. Bridgewater, NJ; 2012 Aug.
2. Van Cutsem E, Tabernero J, Lakomy R et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol . 2012; 30:3499-506. [PubMed 22949147]
3. Tang PA, Cohen SJ, Kollmannsberger C et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res . 2012; 18:6023-31. [PubMed 22977191]
4. Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis . 2012; 15:171-85. [PubMedCentral][PubMed 22302382]
5. Sun W. Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy. J Hematol Oncol . 2012; 5:63. [PubMedCentral][PubMed 23057939]
6. Yoshino T, Yamazaki K, Yamaguchi K et al. A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer. Invest New Drugs . 2012; :. [PubMedCentral]
7. Lockhart AC, Rothenberg ML, Dupont J et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol . 2010; 28:207-14. [PubMed 19949018]
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 125418Orig1s000: Medical review. From FDA website. 2012 Jul 3. [Web]
9. Sanofi-Aventis US, LLC. Bridgewater, NJ: Personal communication.
10. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125418Orig1s000: Summary review. 2013 Sep 23. From FDA website. [Web]
11. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125418Orig1s000: Administration and correspondence documents. 2013 Sep 23. From FDA website. [Web]
12. Regeneron Pharmaceuticals, Inc. Eylea® (aflibercept) injection prescribing information. Tarrytown, NY; 2013 Jun.