Ziv-aflibercept is a fully-humanized recombinant fusion protein that inhibits angiogenesis. It 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. Ziv-aflibercept is indicated in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. Ziv-aflibercept can adversely affect wound healing and should be avoided for at least 4 weeks prior to elective surgery, for 4 weeks after major surgery, and until wounds have adequately healed after any surgery; the safety of resuming ziv-aflibercept after the resolution of wound healing complications has not been established.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific Administration
Injectable Administration
Intravenous 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.
Hypersensitivity reactions were reported less often in previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared with FOLFIRI alone (0.3% vs 0.5%) in a randomized, placebo-controlled, phase III study (n = 1216).
Bleeding or hemorrhage was reported in 38% of previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared to 19% of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216); grade 3 and 4 hemorrhagic events (e.g., GI bleeding, hematuria, and post-procedure hemorrhage) also occurred more often in ziv-aflibercept-treated patients (3% vs. 1%). Rectal bleeding occurred in 5% of patients in the ziv-aflibercept plus FOLFIRI arm compared to 2% of patients in the FOLFIRI alone arm (grade 3 or 4, 0.7% vs. 0.5%, respectively). Additionally, intracranial bleeding and pulmonary hemorrhage or hemoptysis have been reported following ziv-aflibercept use; 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 in patients who develop severe bleeding.
GI perforation was reported in 0.8% of patients with colorectal, pancreatic, or lung cancer who received ziv-aflibercept compared with 0.3% of patients who received placebo in a pooled analysis of 3 randomized, placebo-controlled, phase 3 studies; all events were toxicity grade 3 and 4 in ziv-aflibercept-treated patients (0.8% vs. 0.2%). Additionally, fatal GI perforation has occurred following ziv-aflibercept therapy. Monitor patients for signs and symptoms of GI perforation; discontinue therapy in patients who develop GI perforation.
Grade 3 impaired wound healing occurred in 2 previously treated patients with metastatic colorectal cancer (0.3%) who received ziv-aflibercept plus FOLFIRI compared with no patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216). 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. The safety of resuming ziv-aflibercept after the resolution of wound healing complications has not been established. Other dermatologic adverse events reported more often in the ziv-aflibercept plus FOLFIRI arm compared with the FOLFIRI alone arm were palmar-plantar erythrodysesthesia (hand and foot syndrome) (11% vs. 4%; grade 3/4, 3% vs. 0.5%) and skin hyperpigmentation (8% vs. 3%).
Fistulas (e.g., gastrointestinal fistula, anal fistula, (colo) vaginal fistula, enterocutaneous fistula, and enterovesical fistula) were reported in 1.5% of previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared with 0.5% of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216); grade 3 fistulas also occurred more often in ziv-aflibercept-treated patients (0.3% vs. 0.2%). Discontinue therapy in patients who develop a fistula.
Hypertension was reported in 41% of previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared with 11% of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216). Grade 3 hypertension also occurred more often in ziv-aflibercept-treated patients (19% vs. 1.5%); hypertensive crisis (grade 4 hypertension) was reported in 1 patient (0.2%) who received ziv-aflibercept. Over half of the grade 3 or 4 hypertension cases (54%) occurred within the first 2 cycles of ziv-aflibercept therapy. Monitor blood pressure every 2 weeks or more often if clinically indicated; treat hypertension with antihypertensive therapy. In patients with uncontrolled 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.
Proteinuria was reported in 62% (grade 3 or 4, 8%) of patients with previously treated metastatic colorectal cancer who received ziv-aflibercept plus FOLFIRI compared with 41% (grade 3 or 4, 1%) of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216); nephrotic syndrome occurred in 2 patients (0.5%) who received ziv-aflibercept. Increased serum creatinine levels occurred in 23% of patients in the ziv-aflibercept plus FOLFIRI arm compared with 19% of patients in the FOLFIRI alone arm. Additionally, thrombotic microangiopathy (TMA) was reported in 3 cancer patients (0.13%) across all completed studies (n = 2,258). 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 urine dipstick 2+ or higher for protein. For proteinuria of 2 grams per 24 hours or more, temporarily hold therapy until proteinuria is less than 2 grams per 24 hours. If proteinuria recurs, hold therapy until proteinuria is less than 2 grams per 24 hours then permanently reduce the ziv-aflibercept dose. Discontinue therapy in patients who develop nephrotic syndrome or TMA.
Thromboembolism has been reported with ziv-aflibercept therapy. Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident (stroke), and angina pectoris, were reported in 2.6% (grade 3 or 4, 1.8%) of patients with previously treated metastatic colorectal cancer who received ziv-aflibercept plus FOLFIRI compared with 1.7% (grade 3 or 4, 0.7%) of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216). Discontinue therapy in patients who have an ATE. Venous thromboembolic events (VTE), including deep vein thrombosis and pulmonary embolism (PE), also occurred more often with ziv-aflibercept plus FOLFIRI therapy compared with FOLFIRI alone (9% vs. 7%; grade 3 or 4, 8% vs. 6%). PE was reported in 5% of patients in the ziv-aflibercept plus FOLFIRI arm compared with 3.4% of patients in the FOLFIRI alone arm.
Infection (e.g., urinary tract infection, naso-pharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection) occurred at a higher rate in patients with metastatic colorectal cancer treated with ziv-aflibercept plus FOLFIRI compared to those who received placebo plus FOLFIRI in a randomized clinical trial (46% vs. 33%; grade 3 or 4, 12% vs. 7%). Urinary tract infection was reported separately and occurred in 9% versus 6% of patients, respectively (grade 3 or 4, 0.8% vs. 0.8%).
Diarrhea (69% vs. 57%; grade 3 or 4, 19% vs. 8%) and dehydration (9% vs. 3%; grade 3 or 4, 4% vs. 1%) were reported more often with ziv-aflibercept plus FOLFIRI compared to FOLFIRI alone in patients with previously treated metastatic colorectal cancer in a randomized clinical trial (n = 1,216). There was a higher incidence of diarrhea in geriatric patients (65 years of age or older) compared with younger patients in this study; careful monitoring for diarrhea and dehydration is recommended in geriatric patients. Additional gastrointestinal adverse effects that occurred at a higher rate in the ziv-aflibercept arm include stomatitis (50% vs. 33%; grade 3 or 4, 13% vs. 5%), anorexia (32% vs. 24%; grade 3 or 4, 3% vs. 2%), abdominal pain (27% vs. 24%; grade 3 or 4, 4% vs. 2%), upper abdominal pain (11% vs. 8%; grade 3 or 4, 1% vs. 1%), hemorrhoids (6% vs. 2%), and proctalgia (5% vs. 2%; grade 3 or 4, 0.3% vs. 0.3%).
Headache was reported in 22% of previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared with 9% of patients who received FOLFIRI alone in a randomized, placebo-controlled, phase 3 study (n = 1,216); grade 3 and 4 headache also occurred more often in ziv-aflibercept-treated patients (2% vs. 0.3%).
Respiratory, thoracic, and mediastinal adverse events that were reported more often in patients with previously treated metastatic colorectal cancer who received ziv-aflibercept plus FOLFIRI compared with FOLFIRI alone in a randomized clinical trial (n = 1.216) include epistaxis (28% vs. 7%; grade 3 or 4, 0.2% vs. 0%), dysphonia (25% vs. 3%; grade 3 or 4, 0.5% vs. 0%), dyspnea (12% vs. 9%; grade 3 or 4, 0.8% vs. 0.8%), oropharyngeal pain (8% vs. 3%; grade 3 or 4, 0.2% vs. 0%), and rhinorrhea (6% vs. 2%).
Fatigue (48% vs. 39%; grade 3 or 4, 13% vs. 8%), weight loss (32% vs. 14%; grade 3 or 4, 3% vs. 0.8%), and asthenia (18% vs. 13%; grade 3 or 4, 5% vs. 3%) were reported more often with ziv-aflibercept plus FOLFIRI compared with FOLFIRI alone in patients with previously treated metastatic colorectal cancer in a randomized clinical trial (n = 1,216).
Elevated hepatic enzymes including increased AST (62% vs. 54%; grade 3 or 4, 3% vs. 2%) and ALT (50% vs. 39%; grade 3 or 4, 3% vs. 2%) levels, were reported more often in previously treated metastatic colorectal cancer patients who received ziv-aflibercept plus FOLFIRI compared with patients who received FOLFIRI alone in a randomized clinical trial.
Anti-product antibodies (APA) were present in 1.4% of patients at baseline in a pooled analysis of 15 studies in cancer patients (n = 2,862); antibody formation occurred in 3.1% of patients who received ziv-aflibercept (n = 1,687) compared with 1.7% of those who received placebo (n = 1,134). In evaluable patients who tested positive for APA, neutralizing antibodies were found in 35.4% of patients who received ziv-aflibercept and in 5% of patients who received placebo. The clinical significance of antibody formation is not known, but mean ziv-aflibercept trough concentrations were lower among patients who had neutralizing antibodies compared with the overall population.
Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 0.5% of patients who received ziv-aflibercept as monotherapy or in combination with other chemotherapy (n = 3,795). If RPLS is suspected, confirm the diagnosis with magnetic resonance imaging. Discontinue ziv-aflibercept in patients who develop RPLS. Symptoms usually resolve or improve within days of stopping therapy; however, continued neurologic symptoms or death have been reported after therapy was discontinued.
Osteonecrosis of the jaw has been reported with the use of ziv-aflibercept in postmarketing experience.
Heart failure and decreased ejection fraction have been reported with ziv-aflibercept treatment during postmarketing experience.
Hematologic adverse events were reported more often in patients with metastatic colorectal cancer treated with ziv-aflibercept plus FOLFIRI compared to placebo plus FOLFIRI including leukopenia (78% vs. 72%; grade 3 or 4, 16% vs. 12%), neutropenia (67% vs. 57%; grade 3 or 4, 37% vs. 30%), and thrombocytopenia (48% vs. 35%; grade 3 or 4, 3% vs. 2%). Neutropenic complications including grade 3 or 4 neutropenic fever (4% vs. 2%) and neutropenic infection/sepsis (1.5% vs. 1.2%) were also reported more often in the ziv-aflibercept arm.
Arterial (including aortic) aneurysms, dissections (aortic dissection), and rupture have occurred in postmarketing experience with ziv-aflibercept.
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 3 months 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 3 months 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.
For the treatment of colorectal cancer:
-for the treatment of metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI):
Intravenous dosage:
Adults: 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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Absolute neutrophil count (ANC) less than 1.5 x 109/L: Hold ziv-aflibercept. Resume treatment when ANC is greater than or equal to 1.5 x 109/L
Uncontrolled hypertension: Hold ziv-aflibercept. When blood pressure is controlled, resume therapy at a permanently reduced dose of 2 mg/kg. Discontinue therapy in patients who have hypertensive crisis or develop hypertensive encephalopathy.
Treatment-related proteinuria (2 grams per 24 hours or more): Hold ziv-aflibercept. When proteinuria is less than 2 grams per 24 hours, resume ziv-aflibercept therapy (1st occurrence, resume previous dose; recurrent proteinuria, 2 mg/kg). Discontinue therapy in patients who develop nephrotic syndrome or thrombotic microangiopathy.
Discontinue ziv-aflibercept for:
-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)
Maximum Dosage Limits:
-Adults
4 mg/kg IV every 2 weeks.
-Geriatric
4 mg/kg IV every 2 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.
Patients with Hepatic Impairment Dosing
-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.
Patients with Renal Impairment Dosing
Dosage adjustments are not recommended.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
The clearance of free ziv-aflibercept is not affected by total bilirubin, AST, or ALT based on a population pharmacokinetic analysis that included patients with mild (total bilirubin 1 to 1.5 times the upper limit of normal (ULN) and any AST; n = 63) and moderate (total bilirubin 1.5 to 3 times ULN and any AST; n = 5) hepatic impairment. Ziv-aflibercept exposure was similar in patients with mild and moderate hepatic impairment to patients with normal hepatic function (n = 1,507). No data are available for patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).
Renal Impairment
Based on a population pharmacokinetic analysis, creatinine clearance (CrCL) does not have a clinically important effect on the clearance of free ziv-aflibercept in patients with mild (CrCl 50 to 80 mL/min, n = 549), moderate (CrCl 30 to 50 mL/min, n = 96), and severe renal impairment (CrCl less than 30 mL/min, n = 5). Ziv-aflibercept exposure was similar in patients with any degree of renal impairment to patients with normal renal function (n = 1,507).
Pediatrics
In a dose-escalation, safety, and tolerability study, the mean elimination half-life of free ziv-aflibercept determined after the first dose in pediatric patients (n = 8; age 5 to 17 years) was within the range of values previously observed in adults. The maximum tolerated dose based on body weight was lower in these pediatric patients than the dose known to be safe and effective in adults with metastatic colorectal cancer.
Geriatric
Based on a population pharmacokinetic analysis, age does not have a clinically important effect on the exposure of free ziv-aflibercept.
Gender Differences
Based on a population pharmacokinetic analysis, gender does not have a clinically important effect on the exposure of free ziv-aflibercept.
Ethnic Differences
Based on a population pharmacokinetic analysis, ethnicity does not have a clinically important effect on the exposure of free ziv-aflibercept.
Obesity
Patients weighing 100 kg or more had a 29% increase in systemic exposure to ziv-aflibercept as compared with patients weighing 50 to 100 kg.