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Generic Name: Ziv-aflibercept
Class: Antineoplastic Agents

Warning(s)

  • Hemorrhage
  • Severe hemorrhage (including GI hemorrhage), sometimes fatal, reported.1 Do not use in patients with severe hemorrhage.1 (See Hemorrhage under Cautions.)

  • GI Perforation
  • GI perforation, sometimes fatal, reported.1 If GI perforation occurs, discontinue ziv-aflibercept permanently.1 (See GI Perforation under Cautions.)

  • Surgery and Wound Healing Complications
  • Risk of impaired wound healing.1 Discontinue ziv-aflibercept in patients with compromised wound healing.1 (See Surgery and Wound Healing Complications under Cautions.)

  • Discontinue therapy ≥4 weeks prior to elective surgery.1

  • Do not resume therapy until ≥4 weeks following major surgery and after surgical incision has fully healed.1

Introduction

Antineoplastic agent; a recombinant humanized fusion protein and vascular endothelial growth factor A (VEGF-A), VEGF-B, and placental growth factor (PlGF) antagonist.1

Uses for Zaltrap

Colorectal Cancer

In combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer following failure of oxaliplatin-based chemotherapy.1

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Zaltrap Dosage and Administration

General

  • Do not initiate therapy following surgery unless surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Cautions.)

  • Consult respective manufacturers' labelings or published protocols for information on dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Ziv-aflibercept injection must be diluted prior to administration.1 Use within 4 hours following dilution.1 (See Storage under Stability.)

Administer through a 0.2-mcm polyethersulfone filter; do not use filters made of polyvinylidene fluoride (PVDF) or nylon.1 Use diethylhexyl phthalate (DEHP) plasticized PVC, non-DEHP trioctyltrimellitate (TOTM) PVC, polypropylene, polyethylene-lined PVC, or polyurethane administration sets.1

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.1

Discard any partially used infusion bag.1

Dilution

Withdraw appropriate dose of ziv-aflibercept and dilute in a DEHP plasticized PVC or non-PVC polyolefin infusion bag containing appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield a final concentration of 0.6–8 mg/mL.1 Discard any partially used vial.1

Rate of Administration

Administer over 60 minutes.1

Dosage

Adults

Metastatic Colorectal Cancer
IV

4 mg/kg 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).1 Administer ziv-aflibercept prior to FOLFIRI regimen on the day of treatment.1

Repeat ziv-aflibercept-FOLFIRI combination regimen every 2 weeks; continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity

Discontinue therapy if 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) occurs.1 (See Warnings/Precautions under Cautions.)

Temporarily suspend therapy ≥4 weeks prior to elective surgery.1 Also temporarily interrupt therapy in patients who develop recurrent or severe hypertension or proteinuria1 (see Hypertension and also Proteinuria under Dosage and Administration). Delay therapy in patients with neutrophil count <1500/mm31 (see Neutropenia and Neutropenic Complications under Cautions).

Hypertension

If recurrent or severe hypertension occurs, interrupt therapy until hypertension is controlled; resume therapy at a permanently reduced dosage of 2 mg/kg.1 (See Hypertension under Cautions.)

If hypertensive crisis or hypertensive encephalopathy occurs, discontinue therapy.1

Proteinuria

Interrupt therapy for proteinuria ≥2 g per 24 hours; resume therapy when proteinuria declines to <2 g per 24 hours.1 (See Proteinuria under Cautions.)

If proteinuria recurs, interrupt therapy until proteinuria declines to <2 g per 24 hours; resume therapy at a permanently reduced dosage of 2 mg/kg.1

If nephrotic syndrome or thrombotic microangiopathy occurs, discontinue therapy.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.1 (See Geriatric Use under Cautions.)

Cautions for Zaltrap

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Hemorrhage

Increased risk of bleeding or hemorrhage, including severe and sometimes fatal hemorrhage.1 Grade 3 or 4 hemorrhagic events (e.g., GI hemorrhage, hematuria, postprocedural hemorrhage) reported.1 Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis, including fatal cases, also reported.1

Monitor for signs and symptoms of bleeding.1 Do not initiate ziv-aflibercept in patients with severe hemorrhage.1 Discontinue therapy if severe hemorrhage occurs.1 (See Boxed Warning.)

GI Perforation

GI perforation, sometimes fatal, reported.1

Monitor for signs and symptoms of GI perforation.1 Discontinue ziv-aflibercept if GI perforation occurs.1 (See Boxed Warning.)

Surgery and Wound Healing Complications

Grade 3 compromised wound healing reported.1

Temporarily suspend ziv-aflibercept therapy ≥4 weeks prior to elective surgery.1 Do not resume therapy until ≥4 weeks following major surgery and after surgical incision has fully healed.1 Do not initiate or resume therapy in patients undergoing minor surgery (e.g., central venous access port placement, biopsy, tooth extraction) until after surgical incision has fully healed.1

Discontinue ziv-aflibercept in patients with compromised wound healing.1 (See Boxed Warning.)

Other Warnings and Precautions

Fistula Formation

Increased incidence of fistula formation involving GI and non-GI sites (i.e., anal, enterovesical, enterocutaneous, colovaginal, intestinal) reported.1 2

Discontinue ziv-aflibercept if fistula formation occurs.1

Hypertension

Increased risk of grade 3 or 4 hypertension, including hypertensive crisis.1 Hypertension usually develops during the first 2 cycles of therapy;1 limited data indicate a median time to onset of 3.5 days.7 Hypertension reportedly reversible or manageable following discontinuance of ziv-aflibercept or initiation of appropriate supportive measures.7

Monitor BP every 2 weeks or more frequently as clinically indicated during therapy.1 If hypertension occurs, treat with appropriate antihypertensive therapy, and monitor BP regularly.1 If hypertension recurs or becomes severe, temporarily interrupt therapy until controlled, then resume therapy at a permanently reduced dosage.1 (See Hypertension under Dosage and Administration.) Discontinue ziv-aflibercept if hypertensive crisis or hypertensive encephalopathy occurs.1

Ziv-aflibercept has not been evaluated in patients with NYHA class III or IV heart failure.1

Arterial Thromboembolic Events

Increased incidence of arterial thromboembolic events (e.g., TIA, cerebrovascular accident, angina pectoris), including grade 3 or 4 events, reported.1

Discontinue ziv-aflibercept if an arterial thromboembolic event occurs.1

Proteinuria

Increased incidence of severe proteinuria (including grade 3 or 4 proteinuria), nephrotic syndrome, and thrombotic microangiopathy reported.1 Limited data indicate a median time to onset of 15 days for proteinuria; proteinuria reportedly reversible or manageable following discontinuance of ziv-aflibercept or initiation of appropriate supportive measures.7

Monitor urine dipstick and urinary protein creatinine ratio for development or worsening of proteinuria.1 Further assessment (e.g., 24-hour urine collection) recommended if >1+ urine dipstick reading occurs.1 Interrupt ziv-aflibercept therapy for proteinuria ≥2 g per 24 hours; resume therapy when proteinuria declines to <2 g per 24 hours.1 If proteinuria recurs, interrupt therapy until proteinuria declines to <2 g per 24 hours, then resume therapy at a permanently reduced dosage.1 (See Proteinuria under Dosage and Administration.)

Discontinue ziv-aflibercept if nephrotic syndrome or thrombotic microangiopathy occurs.1

Neutropenia and Neutropenic Complications

Increased incidence of neutropenic complications (e.g., febrile neutropenia, neutropenic infection), including grade 3 or 4 events, reported.1

Monitor CBC counts, including differential, at baseline and prior to initiation of each cycle.1 Delay ziv-aflibercept therapy until neutrophil count is ≥1500/mm3.1

Diarrhea and Dehydration

Increased incidence of grade 3 or 4 diarrhea or dehydration reported.1 Diarrhea more likely to occur in patients ≥65 years of age; monitor such patients closely for diarrhea and dehydration.1

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported.1

If manifestations of RPLS occur, confirm diagnosis by magnetic resonance imaging (MRI) and discontinue ziv-aflibercept therapy.1 Symptoms of RPLS usually resolve or improve within days, but ongoing neurologic sequelae or death have occurred in some patients.1

Immunogenicity

Potential for immunogenicity.1 3 Development of anti-product antibodies and neutralizing antibodies reported.1 Mean free ziv-aflibercept trough concentrations reportedly lower in patients with positive neutralizing antibodies than in overall population; clinical relevance of neutralizing antibodies not established.1

Specific Populations

Pregnancy

Category C.1 (See Advice to Patients.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1 2 8

Geriatric Use

No overall differences in efficacy (i.e., overall survival) in geriatric patients (≥65 years of age) compared with younger adults.1 Increased incidence of diarrhea, dizziness, asthenia, weight loss, and dehydration compared with younger adults.1

Closely monitor for diarrhea and dehydration.1 (See Diarrhea and Dehydration under Cautions.)

Hepatic Impairment

Systemic exposure and clearance not affected by mild or moderate hepatic impairment.1 (See Absorption: Special Populations and also Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Systemic exposure and clearance not affected by mild, moderate, or severe renal impairment.1 (See Absorption: Special Populations and also Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

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 Scr,1 headache.1

Interactions for Zaltrap

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Fluorouracil

Clinically important pharmacokinetic interaction not observed1

Irinotecan

Clinically important pharmacokinetic interaction not observed1

Zaltrap Pharmacokinetics

Absorption

Bioavailability

Free ziv-aflibercept: Exhibits linear pharmacokinetics over dosage range of 2–9 mg/kg.1 Steady-state concentrations reached by the second dose; accumulation ratio is approximately 1.2.1

VEGF-bound ziv-aflibercept: Time to steady-state concentrations estimated to be 70 days (corresponding to sixth dose).8

Special Populations

Age, race, and gender have no clinically important effects on exposure to free ziv-aflibercept.1

Systemic exposure increased by 29% in patients weighing ≥100 kg.1

Mild (total bilirubin concentration >1–1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration >1.5–3 times the ULN and any AST concentration) hepatic impairment does not substantially affect systemic exposure.1 Data not available for patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN and any AST concentration).1

Mild (Clcr of 50–80 mL/minute), moderate (Clcr of 30–50 mL/minute), or severe (Clcr <30 mL/minute) renal impairment does not substantially affect systemic exposure.1

Distribution

Extent

Not known whether ziv-aflibercept is distributed into human milk.1

Elimination

Half-life

Free ziv-aflibercept: Approximately 6 days (range: 4–7 days).1

VEGF-bound ziv-aflibercept: Estimated to be approximately 15 days.8

Special Populations

Mild (total bilirubin concentration >1–1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration >1.5–3 times the ULN and any AST concentration) hepatic impairment does not substantially alter clearance of ziv-aflibercept.1 Data not available for patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN and any AST concentration).1

Mild (Clcr of 50–80 mL/minute), moderate (Clcr of 30–50 mL/minute), or severe (Clcr <30 mL/minute) renal impairment does not substantially affect systemic exposure.1

Stability

Storage

Parenteral

Injection

2–8°C in original carton to protect from light.1

Diluted solution: 2–8°C for up to 4 hours after dilution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • Acts as a soluble decoy receptor that binds to VEGF-A, VEGF-B, and PlGF and inhibits their biologic activity.2 4

  • Ziv-aflibercept (Zaltrap) IV injection contains the same active drug as intravitreal aflibercept (Eylea); because of potential for medication errors, FDA required addition of a prefix to the generic name and approved the name ziv-aflibercept for the US.(R9, R10, R12).

  • VEGF-A, VEGF-B, and PlGF are angiogenic factors that promote endothelial cell proliferation, survival, migration, and vascular permeability.4 5

  • Binding to VEGF-A, VEGF-B, and PlGF prevents these factors from binding to endogenous receptors, reducing neovascularization and vascular permeability.1

  • Binding affinity of ziv-aflibercept for VEGF-A isoforms is higher than that of bevacizumab; ziv-aflibercept also more potent than bevacizumab in inhibiting VEGF-1 and VEGFR-2 activation.4

  • Has been shown to inhibit angiogenesis by inhibiting proliferation of endothelial cells in animals; also has been shown to inhibit growth of xenotransplanted colon tumors in mice.1

Advice to Patients

  • 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 BP and informing clinician if BP 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ziv-aflibercept (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion only

25 mg/mL (100 and 200 mg)

Zaltrap

Sanofi-Aventis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 27, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. [PubMed 22302382]

5. Sun W. Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy. J Hematol Oncol. 2012; 5:63. [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; :.

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.

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.

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.

12. Regeneron Pharmaceuticals, Inc. Eylea (aflibercept) injection prescribing information. Tarrytown, NY; 2013 Jun.

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