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Small Molecule Antineoplastic Multikinase Inhibitors
Intravenous VEGF inhibitorUsed for metastatic colorectal cancer in combination with FOLFIRI in tumors resistant to or that progressed following an oxaliplatin-containing regimenAvoid 4 weeks before elective surgery, 4 weeks after major surgery, and until surgical wounds have adequately healed
ZALTRAP Intravenous Inj Sol: 1mL, 25mg
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.
4 mg/kg IV every 2 weeks.
Safety and efficacy have not been established.
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.
Hazardous Drugs ClassificationNIOSH 2016 List: Group 1 NIOSH (Draft) 2020 List: Table 2Observe 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.
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
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 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.
Impaired wound healing has been reported in patients who received ziv-aflibercept. Discontinue ziv-aflibercept at least 4 weeks prior to elective surgery; do not administer ziv-aflibercept for at least 4 weeks following major surgery and until adequate wound healing. Ziv-aflibercept may be initiated or resumed once the surgical wound is fully 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. The safety of resuming ziv-aflibercept after the resolution of wound healing complications has not been established.
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.
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.
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.
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.
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.
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. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 month after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of ziv-aflibercept. Women who become pregnant while receiving ziv-aflibercept should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of ziv-aflibercept on human fertility, male and female infertility has been observed in animal studies.
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.
neutropenia / Delayed / 37.0-37.0hypertension / Early / 19.0-19.0diarrhea / Early / 19.0-19.0leukopenia / Delayed / 16.0-16.0stomatitis / Delayed / 13.0-13.0fatigue / Early / 13.0-13.0infection / Delayed / 12.0-12.0thromboembolism / Delayed / 2.6-9.0thrombosis / Delayed / 0-9.0proteinuria / Delayed / 8.0-8.0pulmonary embolism / Delayed / 5.0-5.0asthenia / Delayed / 5.0-5.0dehydration / Delayed / 4.0-4.0abdominal pain / Early / 1.0-4.0bleeding / Early / 3.0-3.0palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 3.0-3.0anorexia / Delayed / 3.0-3.0weight loss / Delayed / 3.0-3.0elevated hepatic enzymes / Delayed / 3.0-3.0thrombocytopenia / Delayed / 3.0-3.0stroke / Early / 0-2.6headache / Early / 2.0-2.0angina / Early / 0-1.8gastrointestinal fistula / Delayed / 0-1.5vaginal fistula / Delayed / 0-1.5enterocutaneous fistula / Delayed / 0-1.5GI perforation / Delayed / 0.8-0.8dyspnea / Early / 0.8-0.8nephrotic syndrome / Delayed / 0.5-0.5dysphonia / Delayed / 0.5-0.5leukoencephalopathy / Delayed / 0.5-0.5hypertensive crisis / Early / 0.2-0.2epistaxis / Delayed / 0.2-0.2intracranial bleeding / Delayed / Incidence not knownGI bleeding / Delayed / Incidence not knownosteonecrosis / Delayed / Incidence not knownheart failure / Delayed / Incidence not knownaortic dissection / Delayed / Incidence not known
hemorrhoids / Delayed / 6.0-6.0antibody formation / Delayed / 3.1-3.1hemoptysis / Delayed / Incidence not knownhematuria / Delayed / Incidence not knownimpaired wound healing / Delayed / Incidence not known
skin hyperpigmentation / Delayed / 8.0-8.0rhinorrhea / Early / 6.0-6.0pharyngitis / Delayed / Incidence not known
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. Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents. Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity. 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.
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.