ziv-aflibercept (Rx)

Brand and Other Names:Zaltrap
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 25mg/mL (4-mL, 8-mL single-dose vials)

Colorectal Cancer

Indicated in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen

4 mg/kg IV q2weeks; administer before any component of the FOLFIRI regimen on the day of treatment  

Continue until disease progression or unacceptable toxicity occurs

Dosage Modifications

Discontinue

  • Severe hemorrhage
  • Gastrointestinal perforation
  • Impaired wound healing
  • Fistula formation
  • Hypertensive crisis or hypertensive encephalopathy
  • Arterial thromboembolic events
  • Nephrotic syndrome or thrombotic microangiopathy (TMA)
  • Reversible posterior leukoencephalopathy syndrome (RPLS)

Temporarily suspend

  • At least 4 weeks prior to elective surgery
  • For recurrent or severe hypertension, until controlled; once resumed, permanently reduce dose to 2 mg/kg
  • Proteinuria >2 g/24 hr; resume when proteinuria <2 g/24 hr
  • For recurrent proteinuria, suspend therapy until proteinuria <2 g/24 hr and then permanently reduce dose to 2 mg/kg

Renal impairment

  • No dosage adjustment necessary

Hepatic impairment

  • Mild-to-moderate (total bilirubin >1 to ≤3x ULN and any AST): No dosage adjustment necessary
  • Severe (total bilirubin >3x ULN): Not studied

Safety and efficacy not established

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Adverse Effects

>10%

All grades

  • Leukopenia (78%)
  • Diarrhea (69%)
  • Neutropenia (67%)
  • Proteinuria (62%)
  • AST increased (62%)
  • ALT increased (50%)
  • Stomatitis (50%)
  • Thrombocytopenia (48%)
  • Fatigue (48%)
  • Hypertension (41%)
  • Decreased weight (32%)
  • Decreased appetite (32%)
  • Epistaxis (28%)
  • Abdominal pain (27%)
  • Dysphonia (25%)
  • Increased serum creatinine (23%)
  • Asthenia (18%)
  • Dyspnea (12%)
  • Upper abdominal pain (11%)

Grade 3-4

  • Neutropenia (37%)
  • Diarrhea (19%)
  • Hypertension (19%)
  • Leukopenia (16%)
  • Stomatitis (13%)
  • Fatigue (13%)
  • Palmar-plantar erythrodysesthesia syndrome (11%)

1-10%

All grades

  • Urinary tract infection (9%)
  • Oropharyngeal pain (8%)
  • Skin hyperpigmentation (8%)
  • Venous thromboembolic events (9%)
  • Hemorrhoids (6%)
  • Rectal hemorrhage (5%)
  • Proctalgia (5%)
  • Pulmonary embolism (5%)

Grade 3-4

  • Proteinuria (8%)
  • Asthenia (5%)
  • Abdominal pain (4%)
  • Palmar-plantar erythrodysesthesia syndrome (3%)
  • Thrombocytopenia (3%)
  • AST increased (3%)
  • ALT increased (3%)
  • Decreased weight (3%)
  • Decreased appetite (3%)
  • Upper abdominal pain (1%)

<1%

Grade 3-4

  • Dyspnea (0.8%)
  • Rectal hemorrhage (0.7%)
  • Dysphonia (0.5%)
  • Proctalgia (0.3%)
  • Epistaxis (0.2%)
  • Oropharyngeal pain (0.2%)

Posmarketing Reports

Arterial (including aortic), aneurysms, dissections, and rupture

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Warnings

Contraindications

None

Cautions

Increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events (eg, severe intracranial hemorrhage, pulmonary hemorrhage/hemoptysis); monitor for signs and symptoms of bleeding, and discontinue if needed; do not administer with severe hemorrhage

Gastrointestinal (GI) perforation including fatal GI perforation can occur; monitor for signs and symptoms of bleeding, and discontinue if needed

Grade 3 impaired wound healing was reported; suspend therapy for ≥4 weeks prior to elective surgery; resume therapy ≥4 weeks following major surgery or until surgical wound has healed; for minor surgical procedures (eg, tooth extraction, biopsy, central venous access port placement), resume therapy once surgical wound has healed completely; discontinue in patients with compromised wound healing

Increased risk of fistula formation involving GI and non-GI sites; discontinue if fistula develops

Increased risk of Grade 3-4 hypertension; monitor BP q2weeks or more frequently if indicated; treat with appropriate antihypertensive therapy; temporarily suspend if hypertension uncontrolled, and permanently reduce dose to 2 mg/kg for subsequent cycles once blood pressure normalizes; discontinue with hypertensive encephalopathy or hypertensive crisis

Increased risk of arterial thromboembolic events (eg, TIA, CVA, and angina pectoris); discontinue if thromboembolic event occurs

Increased risk of higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection); monitor CBC with differential count at baseline and prior to initiation of each cycle; delay if neutrophil count ≥1.5 x 109/L

Increased risk of severe diarrhea, especially in patients aged ≥65 years; monitor closely

Increased risk of RPLS (also known as posterior reversible leukoencephalopathy syndrome); confirm RPLS diagnosis with MRI and discontinue if present; RPLS may resolve or improve within days, but some patients have experienced ongoing neurologic sequelae or death

May cause fetal harm based on findings from animal studies and its mechanism of action

Proteinuria

  • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently
  • Monitor by urine dipstick analysis and urinary protein creatinine ratio (UPCR)
  • Obtain 24-hour urine collection in patients with UPCR ≥1; suspend if proteinuria is ≥2 g/24hr, and resume when ≤2 g/24hr; if reoccurs, suspend until ≤2 g/24hr and permanently reduce dose to 2 mg/kg for subsequent cycles; discontinue in patients who develop TMA or nephrotic syndrome
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Pregnancy & Lactation

Pregnancy

Based on findings from animal reproduction studies and its mechanism of action, fetal harm may cause when administered to pregnant women

Insufficient data available in pregnant women exposed to ziv-aflibercept to assess the risk

Advise pregnant women of the potential risk to a fetus

Animal data

  • Administration of ziv-aflibercept during organogenesis was embryotoxic and teratogenic in rabbits at exposure levels ~0.3 times the human exposure at the 4 mg/kg/dose

Pregnancy testing

  • Verify pregnancy status in females of reproductive potential before initiating ziv-aflibercept

Contraception

  • Females or reproductive potential: Use effective contraception during treatment and for 1 month following the last dose

Infertility

  • Advise female and male patients of reproductive potential that treatment may impair reproductive function and fertility

Lactation

There are no data on presence of drug in human milk, or effects on breastfed infant or on milk production

Owing to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 1 month following last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Recombinant fusion protein; soluble receptor that binds to human VEGF-A, VEGF-B and P1GF; binding to these endogenous ligands leads to inhibition of binding and activation of their cognate receptors, which can result in decreased neovascularization and decreased vascular permeability; in animals, shown to inhibit proliferation of endothelial cells, leading to inhibition of growth of new blood vessels

Absorption

Steady state concentrations reached by second dose

Patients weighing ≥100 kg had a 29% increase in systemic exposure compared to patients weighing 50-100 kg

Distribution

Accumulation ratio: 1.2 (4mg/kg q2Week)

Elimination

Half-life: 6 days (4mg/kg q2Week)

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Administration

IV Compatibilities

0.9% NaCl

Dextrose 5% (D5W)

IV Preparation

Clear, colorless to pale yellow solution; do not use if solution if discolored or cloudy

Do not re-enter vial after initial puncture; discard unused portion

Withdraw prescribed dose and dilute in 0.9% NaCl or D5W to achieve final concentration of 0.6–8 mg/mL; use PVC infusion bags containing DEHP or polyolefin infusion bags

IV Administration

Administer diluted solution as IV infusion over 1 hr through a 0.2 micron polyethersulfone filter

Do not use filters made of polyvinylidene fluoride (PVDF) or nylon

Do not combine with other drugs in same infusion bag or IV line

Infusion set compatibility: Administer using infusion set of PVC containing DEHP, DEHP free PVC containing TOTM, polypropylene, polyethylene lined PVC, or polyurethane

Do not administer as an IV bolus

Storage

Unopened vials: Refrigerator at 2-8°C (36-46°F); keep in the original outer carton to protect from light

Diluted bags: May refrigerate at 2-8°C (36-46°F) for up to 4 hr; discard unused portion

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Formulary

FormularyPatient Discounts

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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.