Version May 2024
Ascites, symptomatic; due to malignant ovarian cancer (off-label use; based on limited data): IV: 4 mg/kg every 2 weeks for 2 to 6 months (Ref). Note: Vascular endothelial growth factor (VEGF) blockade should be used with caution in this patient population due to the risk of fatal GI perforation.
Colorectal cancer, metastatic: IV: 4 mg/kg (based on actual body weight) every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]), continue until disease progression or unacceptable toxicity (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Renal impairment prior to treatment initiation:
No dosage adjustment necessary.
Nephrotoxicity during treatment:
Proteinuria (≥2 g/24 hours): Temporarily withhold ziv-aflibercept treatment until proteinuria <2 g/24 hours and then resume at previous dose.
Recurrent proteinuria: Temporarily withhold ziv-aflibercept treatment until proteinuria <2 g/24 hours and then resume with a permanent dose reduction to 2 mg/kg every 2 weeks.
Nephrotic syndrome or thrombotic microangiopathy: Discontinue ziv-aflibercept treatment.
Mild (total bilirubin >1 to 1.5 times ULN and any AST) to moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment: No dosage adjustment necessary.
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Arterial thrombotic events: Discontinue ziv-aflibercept treatment.
Fistula formation: Discontinue ziv-aflibercept treatment.
Gastrointestinal perforation: Discontinue ziv-aflibercept treatment.
Hemorrhage, severe: Discontinue ziv-aflibercept treatment.
Hypertension: If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications (Ref). If ziv-aflibercept is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (Ref).
Uncontrolled hypertension: Temporarily withhold ziv-aflibercept treatment until controlled and then resume with a permanent dose reduction to 2 mg/kg every 2 weeks.
Hypertensive crisis or hypertensive encephalopathy: Discontinue ziv-aflibercept treatment.
Neutropenia: Temporarily withhold ziv-aflibercept (and FOLFIRI) treatment until ANC is ≥1500/mm3.
Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue ziv-aflibercept treatment.
Surgery/wound healing impairment:
Elective surgery: Temporarily withhold ziv-aflibercept treatment for at least 4 weeks prior to elective surgery; do not resume until at least 4 weeks after major surgery AND until wound is fully healed; for minor surgery (eg, biopsy, central venous port placement, tooth extraction), may be resumed after wound is fully healed.
Wound healing impaired: Discontinue ziv-aflibercept treatment.
Note: For toxicities related to FOLFIRI, refer to individual Fluorouracil or Irinotecan monographs.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reactions reported in combination therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI).
>10%:
Cardiovascular: Hypertension (41%)
Dermatologic: Palmar-plantar erythrodysesthesia (11%)
Endocrine & metabolic: Weight loss (32%)
Gastrointestinal: Abdominal pain (27%), decreased appetite (32%), diarrhea (69%, including severe diarrhea), stomatitis (50%; grades 3/4: 13%), upper abdominal pain (11%)
Genitourinary: Proteinuria (62%)
Hematologic & oncologic: Hemorrhage (38%; grades 3/4: 3%), leukopenia (78%; grades 3/4: 16%), neutropenia (67%; grades 3/4: 37%), thrombocytopenia (48%; grades 3/4: 3%)
Hepatic: Increased serum alanine aminotransferase (50%), increased serum aspartate aminotransferase (62%)
Immunologic: Antibody development (3%; neutralizing: 35%)
Infection: Infection (46%)
Nervous system: Fatigue (48%), headache (22%), voice disorder (25%)
Neuromuscular & skeletal: Asthenia (18%)
Renal: Increased serum creatinine (23%)
Respiratory: Dyspnea (12%), epistaxis (28%)
1% to 10%:
Cardiovascular: Arterial thromboembolism (3%), pulmonary embolism (5%), venous thromboembolism (9%, including deep vein thrombosis)
Dermatologic: Hyperpigmentation (8%)
Endocrine & metabolic: Dehydration (9%)
Gastrointestinal: Gastrointestinal hemorrhage (grades 3/4: ≤3%), hemorrhoids (6%), rectal pain (5%)
Genitourinary: Hematuria (grades 3/4: ≤3%), urinary tract infection (9%)
Hematologic & oncologic: Febrile neutropenia (grades 3/4: 4%), neutropenic infection (grades 3/4: ≤2%), postprocedural hemorrhage (grades 3/4: ≤3%), rectal hemorrhage (5%)
Infection: Neutropenic sepsis (grades 3/4: ≤2%)
Respiratory: Oropharyngeal pain (8%), rhinorrhea (6%)
Miscellaneous: Fistula (2%)
<1%:
Cardiovascular: Hypertensive crisis
Gastrointestinal: Gastrointestinal perforation
Genitourinary: Nephrotic syndrome
Hematologic & oncologic: Thrombotic microangiopathy
Hypersensitivity: Severe hypersensitivity reaction
Nervous system: Reversible posterior leukoencephalopathy syndrome
Miscellaneous: Wound healing impairment
Frequency not defined:
Cardiovascular: Angina pectoris, cerebrovascular accident
Gastrointestinal: Tooth infection
Hematologic & oncologic: Pulmonary hemorrhage
Local: Catheter infection
Nervous system: Intracranial hemorrhage
Respiratory: Hemoptysis, nasopharyngitis, pneumonia, upper respiratory tract infection
Postmarketing:
Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, cardiac failure, coronary artery dissection, myocardial rupture (arterial rupture and aortic rupture), reduced ejection fraction
Neuromuscular & skeletal: Osteonecrosis of the jaw
There are no contraindications listed in the manufacturer’s labeling.
Concerns related to adverse effects:
• Bone marrow suppression: A higher incidence of neutropenia and complications due to neutropenia (neutropenic fever and infection), including grade 3 and 4 events, occurred with ziv-aflibercept. Leukopenia and thrombocytopenia have also occurred. Monitor CBC with differential (baseline and prior to each cycle); delay treatment until ANC is ≥1,500/mm3.
• Diarrhea: Severe diarrhea and dehydration (grades 3 and 4) have been reported with ziv-aflibercept. The incidence of diarrhea is increased in patients ≥65 years of age; monitor elderly patients closely for diarrhea.
• Fistula formation: The risk for GI and non-GI fistulas is increased with ziv-aflibercept. Fistula sites have included anal, enterovesical, enterocutaneous, colovaginal, and intestinal. Discontinue ziv-aflibercept in patients who develop fistula.
• GI perforation: GI perforation, including fatal GI perforation, may occur in patients receiving ziv-aflibercept. Discontinue ziv-aflibercept therapy in patients who experience GI perforation. Monitor for signs/symptoms of GI perforation.
• Hemorrhage: The risk for hemorrhage is increased with ziv-aflibercept. Severe and sometimes fatal hemorrhage, including GI bleeding, has been reported in patients who have received ziv-aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI). Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ziv-aflibercept to patients with severe hemorrhage. Discontinue if severe hemorrhage develops. Grade 3 and 4 hemorrhagic events, including hematuria and postprocedural hemorrhage, have been reported. Intracranial hemorrhage and pulmonary hemorrhage/hemoptysis (including fatal events) have also occurred.
• Hypertension: The risk for grades 3 or 4 hypertension is increased with ziv-aflibercept. Onset is generally within the first 2 treatment cycles. Monitor blood pressure every 2 weeks (more frequently if clinically indicated). Manage with appropriate antihypertensive therapy (may require adjustment of existing antihypertensives). Temporarily withhold ziv-aflibercept treatment with uncontrolled hypertension; may reinitiate with permanent dose reduction when controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. Patients with NYHA class III or IV heart failure were excluded from clinical trials.
• Proteinuria/nephrotic syndrome: Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been associated with ziv-aflibercept. Evaluate for proteinuria during treatment with urine dipstick and/or urinary protein creatinine ratio (UPCR); if dipstick ≥2+ for protein or UPCR >1, obtain 24-hour urine collection. Withhold ziv-aflibercept for proteinuria ≥2 g per 24 hours; for recurrent proteinuria, withhold treatment until <2 g per 24 hours and then resume with permanent dose reduction. Discontinue treatment for nephrotic syndrome or TMA.
• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome have been reported. Confirm diagnosis with MRI; discontinue ziv-aflibercept if verified. Symptoms generally resolve or improve within days, although persistent neurologic symptoms and death have been reported
• Thromboembolism: Arterial thrombotic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina, have occurred. Discontinue ziv-aflibercept in patients who experience ATEs.
• Wound healing impairment: Severely compromised wound healing may occur in patients receiving ziv-aflibercept with FOLFIRI. Discontinue ziv-aflibercept in patients with compromised wound healing. Suspend ziv-aflibercept for at least 4 weeks prior to elective surgery, and do not resume ziv-aflibercept for at least 4 weeks after major surgery AND until the surgical wound is completely healed. For minor surgeries (eg, central venous access port placement, biopsy, tooth extraction), ziv-aflibercept may be resumed or initiated as soon as the surgical wound is fully healed. The safety of resuming ziv-aflibercept treatment after resolution of wound healing complications has not been established.
Special populations:
• Older adult: Certain adverse events, such as diarrhea, dizziness, weakness, weight loss, and dehydration, occurred at a higher incidence in elderly patients compared to younger adults; monitor closely during treatment.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Zaltrap: 100 mg/4 mL (4 mL); 200 mg/8 mL (8 mL)
No
Solution (Zaltrap Intravenous)
100 mg/4 mL (per mL): $480.00
200 mg/8 mL (per mL): $480.00
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Zaltrap: 100 mg/4 mL ([DSC]); 200 mg/8 mL ([DSC])
IV: Infuse over 1 hour. Do not administer as an IV push or bolus. Administer prior to any FOLFIRI component. Do not administer other medications through the same intravenous line.
Infuse via a 0.2 micron polyethersulfone filter; do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Administer with one of the following types of infusion sets: Polyvinyl chloride (PVC) containing DEHP, DEHP-free PVC containing trioctyl-trimellitate (TOTM), polypropylene, polyethylene lined PVC, or polyurethane.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]) that is resistant to or has progressed on an oxaliplatin-based regimen.
Ascites (symptomatic; due to malignant ovarian cancer)
Ziv-aflibercept may be confused with aflibercept
This medication is in a class the Institute for Safe Medical Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Verify pregnancy status prior to use. Patients who could become pregnant should use effective contraception during therapy and for 3 months following the last ziv-aflibercept dose.
Ziv-aflibercept may impair reproductive function in patients of reproductive potential.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to ziv-aflibercept may cause fetal harm. Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor; VEGF is required to achieve and maintain normal pregnancies (Peracha 2016).
It is not known if ziv-aflibercept is present in breast milk.
Aflibercept is present in breast milk following intravitreal administration (Juncal 2020).
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends to discontinue breastfeeding during ziv-aflibercept therapy and for 1 month following the last ziv-aflibercept dose.
CBC with differential (baseline and prior to each cycle); urine protein (dipstick analysis and/or urinary protein creatinine ratio [UPCR], obtain 24-hour urine collection if dipstick ≥2+ for protein or UPCR >1); blood pressure (every 2 weeks; more frequently if clinically indicated). Evaluate pregnancy status prior to use in patients who could become pregnant. Monitor for signs/symptoms of hemorrhage or GI perforation; monitor elderly patients closely for diarrhea and/or dehydration. Monitor wounds for healing impairment.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017], ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months during the first year and every 6 to 12 months thereafter for moderate-risk patients) (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Ziv-aflibercept is a recombinant fusion protein which is comprised of portions of binding domains for vascular endothelial growth factor (VEGF) receptors 1 and 2, attached to the Fc portion of human IgG1. Ziv-aflibercept acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF) which prevent VEGF receptor binding/activation to their receptors (an action critical to angiogenesis), thus leading to antiangiogenesis and tumor regression.
Half-life elimination: ~6 days (range: 4 to 7 days)
Body weight: Patients weighing ≥100 kg had a 29% increase in systemic exposure compared with patients weighing 50 to 100 kg.
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