ZALTRAP

Small Molecule Antineoplastic Multikinase Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Dosing of ziv-aflibercept should be based on actual body weight.
Administer prior to fluorouracil, leucovorin, and irinotecan (FOLFIRI) chemotherapy.
Visually inspect parenteral products for particulate matter and discoloration prior to administration.
 
Dilution and Preparation:
Withdraw the calculated dose of ziv-aflibercept from the vial and add to 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.6 to 8 mg/mL; use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DHEP) or polyolefin infusion bags.
Do not re-enter the vial after first puncture; discard any unused portion in the vial.
Do not mix or combine with other drugs in the same infusion bag.
The diluted solution may be stored refrigerated at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit) for up to 24 hours, or at controlled room temperature (20 to 25 degrees Celsius, or 68 to 77 degrees Fahrenheit) for up to 8 hours. Discard any unused portion in the infusion bag.
 
Intravenous Infusion:
Administer the diluted solution IV over 1 hour using a 0.2 micron polyethersulfone filter; do not use nylon or polyvinylidene fluoride (PVDF) filters.
Do not administer as an IV push or bolus.
Do not mix or combine with other drugs in the same IV line.
Administer using an infusion set made of one of the following: PVC containing DEHP, DEHP free PVC containing trioctyl-trimellitate (TOTM), polypropylene, polyethylene lined PVC, or polyurethane.

neutropenia / Delayed / 37.0-37.0
hypertension / Early / 19.0-19.0
diarrhea / Early / 19.0-19.0
leukopenia / Delayed / 16.0-16.0
stomatitis / Delayed / 13.0-13.0
fatigue / Early / 13.0-13.0
infection / Delayed / 12.0-12.0
thromboembolism / Delayed / 2.6-9.0
thrombosis / Delayed / 0-9.0
proteinuria / Delayed / 8.0-8.0
pulmonary embolism / Delayed / 5.0-5.0
asthenia / Delayed / 5.0-5.0
dehydration / Delayed / 4.0-4.0
abdominal pain / Early / 1.0-4.0
bleeding / Early / 3.0-3.0
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 3.0-3.0
anorexia / Delayed / 3.0-3.0
weight loss / Delayed / 3.0-3.0
elevated hepatic enzymes / Delayed / 3.0-3.0
thrombocytopenia / Delayed / 3.0-3.0
stroke / Early / 0-2.6
headache / Early / 2.0-2.0
angina / Early / 0-1.8
gastrointestinal fistula / Delayed / 0-1.5
vaginal fistula / Delayed / 0-1.5
enterocutaneous fistula / Delayed / 0-1.5
GI perforation / Delayed / 0.8-0.8
dyspnea / Early / 0.8-0.8
nephrotic syndrome / Delayed / 0.5-0.5
dysphonia / Delayed / 0.5-0.5
leukoencephalopathy / Delayed / 0.5-0.5
hypertensive crisis / Early / 0.2-0.2
epistaxis / Delayed / 0.2-0.2
intracranial bleeding / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
osteonecrosis / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
aortic dissection / Delayed / Incidence not known

hemorrhoids / Delayed / 6.0-6.0
antibody formation / Delayed / 3.1-3.1
hemoptysis / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known

skin hyperpigmentation / Delayed / 8.0-8.0
rhinorrhea / Early / 6.0-6.0
pharyngitis / Delayed / Incidence not known

ZALTRAP

Rx

Intravenous VEGF inhibitor
Used for metastatic colorectal cancer in combination with FOLFIRI in tumors resistant to or that progressed following an oxaliplatin-containing regimen
Avoid 4 weeks before elective surgery, 4 weeks after major surgery, and until surgical wounds have adequately healed

4 mg/kg of actual body weight IV over 1 hour, followed by FOLFIRI on day 1, every 2 weeks until disease progression or unacceptable toxicity; FOLFIRI consists of irinotecan (180 mg/m2 IV over 90 minutes) infused via Y-site with leucovorin (400 mg/m2 IV over 2 hours), followed by fluorouracil (400 mg/m2 IV bolus followed by 2,400 mg/m2 as a 46-hour continuous IV infusion). The addition of ziv-aflibercept to FOLFIRI significantly improved median overall survival (13.5 months vs. 12.06 months) and progression-free survival (6.9 months vs. 4.67 months) compared with FOLFIRI alone in patients with metastatic colorectal cancer who were resistant to or had progressed during or within 6 months of an oxaliplatin-containing regimen in a randomized, double-blind, placebo-controlled, phase 3 trial (the VELOUR study). In a preplanned subgroup analysis, OS was not improved in the 373 patients who had previously received bevacizumab in combination with oxaliplatin-containing therapy.

Mild (total bilirubin 1 to 1.5 times the upper limit of normal (ULN) and any AST) and moderate (total bilirubin 1.5 to 3 times ULN and any AST) hepatic impairment: No dosage adjustment recommended.
Severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST): Ziv-aflibercept has not been studied in this population.

Dosage adjustments are not recommended.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

ZALTRAP Intravenous Inj Sol: 1mL, 25mg

4 mg/kg IV every 2 weeks.

4 mg/kg IV every 2 weeks.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Ziv-aflibercept is an angiogenesis inhibitor. It is a fully humanized recombinant fusion protein that acts as a soluble receptor to bind vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factors 1 and 2, which prevents other native receptors from binding. Inhibition of native receptor binding can result in decreased neovascularization and decreased vascular permeability. In animals, ziv-aflibercept inhibited the growth of new blood vessels through inhibition of endothelial cell proliferation. Also, in mice, ziv-aflibercept inhibited the growth of xenotransplanted colon tumors.

Ziv-Aflibercept is administered by intravenous infusion. The elimination half-life of free ziv-aflibercept was approximately 6 days (range, 4 to 7 days) after 4 mg/kg IV every two weeks. Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetic parameters in the dose range of 2 to 9 mg/kg.

Steady state concentrations of free ziv-aflibercept were reached by the second dose of 4 mg/kg IV every two weeks. The accumulation ratio for free ziv-aflibercept was approximately 1.2.

Pregnancy should be avoided by females of reproductive potential during ziv-aflibercept treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, ziv-aflibercept can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving ziv-aflibercept should be apprised of the potential hazard to the fetus. Administration of ziv-aflibercept to rabbits during organogenesis was embryotoxic and teratogenic at exposure levels approximately 0.3 times the human exposure at the 4 mg/kg dose. Doses at this level or higher given during organogenesis resulted in an increase in postimplantation loss and external (e.g., anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and anal atresia), visceral (heart, great vessels, and arteries), and skeletal fetal malformations (e.g., fused vertebrae, sternebrae, and ribs, supernumerary arches and ribs, and incomplete ossification).

Due to the potential for serious adverse reactions in nursing infants from ziv-aflibercept, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose. It is not known whether ziv-aflibercept is present in human milk, although many drugs are excreted in human milk.