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  • CLASSES

    Other Antineoplastic Agents

    BOXED WARNING

    Bleeding, GI bleeding, intracranial bleeding

    Severe bleeding has occurred with ziv-aflibercept use, including GI bleeding, intracranial bleeding, and pulmonary hemorrhage/hemoptysis; some cases were fatal. Monitor patients for signs and symptoms of bleeding. Do not use ziv-aflibercept in patients with severe hemorrhage and discontinue therapy if patients develop severe bleeding.

    GI perforation

    GI perforation has been reported with ziv-aflibercept use; some cases were fatal. Monitor patients for signs and symptoms of GI perforation; discontinue therapy if patients develop GI perforation.

    Dental work, surgery, wound dehiscence

    Compromised wound healing/wound dehiscence has been reported in patients who received ziv-aflibercept. Temporary suspension of therapy is recommended at least 4 weeks before elective surgery. After major surgery, do not restart ziv-aflibercept for at least 4 weeks and until the surgical wound is entirely healed. Ziv-aflibercept may be initiated/resumed once the surgical wound is entirely healed after minor surgery (e.g., central venous access port placement, biopsy, dental work such as tooth extraction). Discontinue therapy if patients develop impaired wound healing.

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized recombinant fusion protein that binds with high affinity to VEGF-A, VEGF-B, and placental growth factors and inhibits angiogenesis
    Approved for metastatic colorectal cancer in combination with FOLFIRI chemotherapy in tumors resistant to or that progressed following an oxaliplatin-containing regimen
    Black box warning for gastrointestinal perforation, surgery/wound healing complications, and hemorrhage

    COMMON BRAND NAMES

    ZALTRAP

    HOW SUPPLIED

    ZALTRAP Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen, in combination with 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI).
    Intravenous
    Adults

    4 mg/kg IV over 1 hour, followed by FOLFIRI (irinotecan 180 mg/m2 IV over 90 minutes and leucovorin 400 mg/m2 IV over 2 hours (infused at the same time via Y-line), followed by 5-FU 400 mg/m2 IV bolus then 2,400 mg/m2 as a 46-hour continuous IV infusion) on day 1, every 2 weeks until disease progression or unacceptable toxicity. Administer ziv-aflibercept prior to FOLFIRI. In a randomized, double-blind, placebo-controlled, phase III study (the VELOUR study), treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity. The median overall survival (OS) time (primary endpoint) was significantly improved with ziv-aflibercept plus FOLFIRI compared with FOLFIRI alone (13.5 vs. 12.06 months; hazard ratio (HR) = 0.817; 95% CI, 0.713 to 0.937; p = 0.0032) in 1,226 metastatic colorectal cancer patients who were resistant to or had progressed during or within 6 months of an oxaliplatin-containing regimen. Additionally, the progression-free survival (PFS) time was significantly improved with ziv-aflibercept plus FOLFIRI compared with FOLFIRI alone (6.9 vs. 4.67 months; HR = 0.758; 95% CI, 0.661 to 0.869; p < 0.0001). In a preplanned subgroup analysis, OS was not improved in the 373 patients who had previously received bevacizumab in combination with oxaliplatin-containing therapy (HR = 0.862; 95% CI, 0.673 to 1.104).

    MAXIMUM DOSAGE

    Adults

    4 mg/kg IV q2 weeks.

    Geriatric

    4 mg/kg IV q2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available. Ziv-aflibercept has not been studied in patients with severe hepatic impairment (total bilirubin greater than 3 times the upper limit of normal and any AST/ALT).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration
    Intravenous Administration

    Administer prior to 5-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 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.

    STORAGE

    ZALTRAP:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding, GI bleeding, intracranial bleeding

    Severe bleeding has occurred with ziv-aflibercept use, including GI bleeding, intracranial bleeding, and pulmonary hemorrhage/hemoptysis; some cases were fatal. Monitor patients for signs and symptoms of bleeding. Do not use ziv-aflibercept in patients with severe hemorrhage and discontinue therapy if patients develop severe bleeding.

    GI perforation

    GI perforation has been reported with ziv-aflibercept use; some cases were fatal. Monitor patients for signs and symptoms of GI perforation; discontinue therapy if patients develop GI perforation.

    Dental work, surgery, wound dehiscence

    Compromised wound healing/wound dehiscence has been reported in patients who received ziv-aflibercept. Temporary suspension of therapy is recommended at least 4 weeks before elective surgery. After major surgery, do not restart ziv-aflibercept for at least 4 weeks and until the surgical wound is entirely healed. Ziv-aflibercept may be initiated/resumed once the surgical wound is entirely healed after minor surgery (e.g., central venous access port placement, biopsy, dental work such as tooth extraction). Discontinue therapy if patients develop impaired wound healing.

    Encephalopathy

    Reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome (PRES), has been reported in patients treated with ziv-aflibercept. Discontinue ziv-aflibercept in patients suspected of developing RPLS. Patients with headache, lethargy, seizures, confusion, blindness, and other visual or neurologic disturbances should be evaluated for RPLS with magnetic resonance imaging (MRI). Mild to severe hypertension may also be present. Symptoms usually resolve or improve within days of treatment discontinuation; however, some patients have experienced ongoing neurologic sequelae.

    Hypertension

    Severe hypertension, including hypertensive crisis, has been reported with ziv-aflibercept use. Monitor blood pressure every 2 weeks or more often if clinically indicated; treat hypertension with antihypertensive therapy. In patients with recurrent or severe hypertension, temporarily hold therapy until blood pressure is controlled and then permanently reduce the ziv-aflibercept dose. Discontinue therapy in patients who develop hypertensive crisis or hypertensive encephalopathy. Over half of the grade 3 or 4 hypertension cases occurred within the first 2 cycles of ziv-aflibercept therapy. Use ziv-aflibercept with caution in patients with pre-existing hypertension.

    Proteinuria

    Severe proteinuria, including nephrotic syndrome or thrombotic microangiopathy (TMA), has been reported with ziv-aflibercept use. Monitor urine protein by urine dipstick analysis and urinary protein creatinine ratio (UPCR); obtain a 24-hour urine collection for a UPCR higher than 1 or a urine dipstick of 2+ or higher for protein. For proteinuria of 2 grams/24 hours, temporarily hold therapy until proteinuria is less than 2 grams/24 hours. If proteinuria recurs, hold therapy until proteinuria is less than 2 grams/24 hours then permanently reduce the ziv-aflibercept dose. Discontinue therapy in patients who develop nephrotic syndrome or TMA.

    Infection, neutropenia

    Neutropenic complications, including febrile neutropenia and neutropenic infection/sepsis, has been reported with ziv-aflibercept use. Monitor complete blood counts with differential at baseline and prior to each cycle of therapy; hold ziv-aflibercept/FOLFIRI therapy until the neutrophil count is greater than or equal to 1.5 X 109/L.

    Geriatric

    There was a higher incidence of toxicity (>= 5%) including diarrhea, dizziness, asthenia, weight loss, and dehydration with ziv-aflibercept plus 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) therapy in geriatric patients (>= 65 years of age) with metastatic colorectal cancer compared with younger patients in a randomized study. Although no dosage adjustment is necessary in elderly patients, careful monitoring for diarrhea and dehydration is recommended in this population.

    Contraception requirements, infertility, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ziv-aflibercept treatment. Ziv-aflibercept can be teratogenic if taken by the mother during pregnancy; male-mediated teratogenicity is also possible. Females of reproductive potential should avoid pregnancy and undergo pregnancy testing prior to initiation of treatment with ziv-aflibercept. Females and males should use highly effective contraception during and for at least 3 months after treatment. Women who become pregnant while receiving ziv-aflibercept should be apprised of the potential hazard to the fetus. In addition, based on animal data, ziv-aflibercept may cause impaired fertility or infertility. Specifically, ziv-aflibercept inhibited ovarian function and follicular development in monkeys, and caused alterations in sperm morphology and decreased sperm motility. These effects were observed at all doses tested including the lowest tested dose, which was approximately 60% of the AUC in humans at the recommended dose. Reversibility was observed within 18 weeks after cessation of treatment.

    Pregnancy

    Ziv-aflibercept is classified as FDA pregnancy category C. No adequate studies of ziv-aflibercept exist in pregnant women. Ziv-aflibercept was embryotoxic and teratogenic in rabbits at exposure levels that were less than recommended human exposure levels. In rabbits, doses of 3 mg/kg IV resulted in an AUC that was 30% of the human exposure; increasing doses resulted in more frequent and severe fetal abnormalities. Adverse embryo-fetal effects included increased incidences of post-implantation losses and external (e.g., anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (e.g., heart, great vessels, and arteries), and skeletal (e.g., incomplete ossification, supernumerary arches and ribs, and fused vertebrae, sternebrae, and ribs) fetal malformations. Use ziv-aflibercept during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    Breast-feeding

    According to the manufacturer, ziv-aflibercept or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from ziv-aflibercept. It is not known if ziv-aflibercept is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    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
    thrombocytopenia / 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
    stroke / Early / 0-2.6
    headache / Early / 2.0-2.0
    angina / Early / 0-1.8
    gastrointestinal fistula / Delayed / 0-1.5
    enterocutaneous fistula / Delayed / 0-1.5
    vaginal 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

    Moderate

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

    Mild

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

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Ziv-aflibercept is classified as FDA pregnancy category C. No adequate studies of ziv-aflibercept exist in pregnant women. Ziv-aflibercept was embryotoxic and teratogenic in rabbits at exposure levels that were less than recommended human exposure levels. In rabbits, doses of 3 mg/kg IV resulted in an AUC that was 30% of the human exposure; increasing doses resulted in more frequent and severe fetal abnormalities. Adverse embryo-fetal effects included increased incidences of post-implantation losses and external (e.g., anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (e.g., heart, great vessels, and arteries), and skeletal (e.g., incomplete ossification, supernumerary arches and ribs, and fused vertebrae, sternebrae, and ribs) fetal malformations. Use ziv-aflibercept during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    According to the manufacturer, ziv-aflibercept or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from ziv-aflibercept. It is not known if ziv-aflibercept is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Intravenous Route

    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.