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Ziv-Aflibercept (Systemic)

Pronunciation

(ziv a FLIB er sept)

Index Terms

  • Aflibercept I.V.
  • Vascular Endothelial Growth Factor Trap
  • VEGF Trap
  • VEGF Trap R1R2

Dosage Forms

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) [contains mouse (murine) and/or hamster protein]

Brand Names: U.S.

  • Zaltrap

Pharmacologic Category

  • Antineoplastic Agent
  • Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Also known as VEGF-trap, 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)

Special Populations Note

Body weight: Patients weighing 100 kg or greater had a 29% increase in systemic exposure compared with patients weighing 50 to 100 kg.

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]) in patients who are resistant to or have progressed on an oxaliplatin-based regimen

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Colorectal cancer, metastatic: IV: 4 mg/kg every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRI]), continue until disease progression or unacceptable toxicity

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, need for adjustment is not likely because exposure in patients with mild, moderate, and severe impairment was similar to that of patients with normal renal function.

Dosing: Hepatic Impairment

Mild (total bilirubin >1 to 1.5 times ULN) to moderate (total bilirubin >1.5 to 3 times ULN) impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, need for adjustment is not likely because exposure was similar to that of patients with normal hepatic function.

Severe impairment (total bilirubin >3 times ULN): There are no dosage adjustments provided in the manufacturer’s labeling (no data available).

Dosing: Adjustment for Toxicity

Arterial thrombotic events: Discontinue treatment.

Fistula formation: Discontinue treatment.

Gastrointestinal perforation: Discontinue treatment.

Hemorrhage, severe: Discontinue treatment.

Hypertension:

Recurrent or severe hypertension: Temporarily withhold treatment until controlled and then resume with a permanent dose reduction to 2 mg/kg every 2 weeks.

Hypertensive crisis or hypertensive encephalopathy: Discontinue treatment.

Neutropenia: Temporarily withhold treatment until ANC is ≥1500/mm3.

Renal effects:

Proteinuria (≥2 g/24 hours): Temporarily withhold treatment until proteinuria <2 g/24 hours and then resume at previous dose.

Recurrent proteinuria: Temporarily withhold 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 treatment

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue treatment.

Surgery/wound healing impairment:

Elective surgery: Temporarily withhold 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 treatment.

Note: For toxicities related to FOLFIRI, refer to individual Fluorouracil or Irinotecan monographs.

Reconstitution

Prior to infusion, dilute in D5W or NS to a final concentration of 0.6 to 8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing DEHP or polyolefin bags. After initial vial puncture, do not re-enter; discard any unused portion of the vial. Do not mix with other medications.

Administration

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.

Compatibility

Stable in D5W, NS; do not mix with or infuse in the same IV line with other products

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light (store in original outer carton).

Solutions diluted for infusion in D5W or NS may be stored in refrigerator for up to 24 hours, or at 20°C to 25°C (68°F to 77°F) for up to 8 hours.

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Adverse Reactions

Note: Reactions reported in combination therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI).

>10%:

Cardiovascular: Hypertension (41%; grade 3: 19%; grade 4: <1%)

Central nervous system: Fatigue (48%), voice disorder (25%; grades 3/4: <1%), headache (22%)

Dermatologic: Palmar-plantar erythrodysesthesia (11%)

Endocrine & metabolic: Weight loss (32%)

Gastrointestinal: Diarrhea (69%; grades 3/4: 19%), stomatitis (50%), decreased appetite (32%), abdominal pain (27%), upper abdominal pain (11%)

Genitourinary: Proteinuria (62%, grades 3/4: 8%)

Hematologic: Leukopenia (78%; grades 3/4: 16%), neutropenia (67%; grades 3/4: 37%), thrombocytopenia (48%; grades 3/4: 3%), hemorrhage (38%; grades 3/4: 3%)

Hepatic: Increased serum AST (62%), increased serum ALT (50%)

Infection: Infection (46%, grades 3/4: 12%)

Neuromuscular & skeletal: Weakness (18%; grades 3/4: 5%)

Renal: Increased serum creatinine (23%)

Respiratory: Epistaxis (28%; grades 3/4: <1%), dyspnea (12%)

1% to 10%:

Cardiovascular: Venous thromboembolic events (9%), pulmonary embolism (5%), arterial thromboembolism (3%; grades 3/4: 2%)

Central nervous system: Reversible posterior encephalopathy syndrome (1%)

Dermatologic: Hyperpigmentation (8%)

Endocrine & metabolic: Dehydration (9%; grades 3/4: 4%)

Gastrointestinal: Hemorrhoids (6%), proctalgia (5%), rectal hemorrhage (5%; grades 3/4: <1%), rectal pain (5%)

Genitourinary: Urinary tract infection (9%), nephrotic syndrome (1%)

Hematologic: Febrile neutropenia (grades 3/4: 4%)

Immunologic: Immunogenicity (3%)

Infection: Neutropenic sepsis

Respiratory: Oropharyngeal pain (8%), rhinorrhea (6%)

Miscellaneous: Fistula formation (2%; grades 3/4: <1%)

Frequency not defined:

Central nervous system: Intracranial hemorrhage (severe)

Hematologic & oncologic: Pulmonary hemorrhage

<1% (Limited to important or life-threatening): Osteonecrosis of the jaw, reduced ejection fracture, thrombotic thrombocytopenic purpura, wound healing impairment

ALERT: U.S. Boxed Warning

Hemorrhage:

Severe and sometimes fatal hemorrhage, including GI hemorrhage, has been reported in patients who have received ziv-aflibercept in combination with irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI). Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ziv-aflibercept to patients with severe hemorrhage.

GI perforation:

GI perforation, including fatal GI perforation, can occur in patients receiving ziv-aflibercept. Discontinue ziv-aflibercept therapy in patients who experience GI perforation.

Compromised wound healing:

Severe compromised wound healing can occur in patients receiving ziv-aflibercept with irinotecan, leucovorin, and 5-fluorouracil. 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 following major surgery and until the surgical wound is fully healed.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: A higher incidence of neutropenia and complications due to neutropenia (neutropenic fever and infection) occurred in patients receiving ziv-aflibercept. Leukopenia and thrombocytopenia were also observed in clinical trials. Monitor CBC with differential (baseline and prior to each cycle); delay treatment until ANC is ≥1,500/mm3.

• Diarrhea: Severe diarrhea and dehydration have been reported. The incidence of diarrhea is increased in patients ≥65 years of age; monitor elderly patients closely for diarrhea.

• Fistula formation: The risk for gastrointestinal (GI) and non-GI fistulas is increased with ziv-aflibercept. Fistula sites have included anal, enterovesical, enterocutaneous, colovaginal, and intestinal. Discontinue in patients who develop fistula.

• Gastrointestinal perforation: [U.S. Boxed Warning]: Severe or fatal GI perforation is a possibility; discontinue ziv-aflibercept if GI perforation occurs. Monitor for signs/symptoms of GI perforation.

• Hemorrhage: The risk for hemorrhage is increased with ziv-aflibercept. [U.S. Boxed Warning]: Severe and occasionally fatal hemorrhage, including GI bleeding, has been reported with ziv-aflibercept/FOLFIRI. Monitor for signs and symptoms of GI and other severe bleeding events. Do not administer to patients with severe hemorrhage. Discontinue if severe hemorrhage develops. Hemorrhagic events have also included hematuria, postprocedural hemorrhage, intracranial hemorrhage, and pulmonary hemorrhage/hemoptysis.

• Hypertension: The risk for grades 3/4 hypertension is increased. Onset is generally within the first 2 treatment cycles. Monitor blood pressure every 2 weeks (more frequently if clinically indicated). Treat with appropriate antihypertensive therapy (may require adjustment of existing antihypertensives). Temporarily withhold treatment with uncontrolled hypertension; may reinitiate with permanent dose reduction when controlled. Discontinue for hypertensive crisis or encephalopathy. Patients with NYHA class III or IV heart failure were excluded from clinical trials.

• Proteinuria/nephrotic syndrome: 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 (RPLS): Cases of RPLS 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 accidents, and angina have occurred. Discontinue ziv-aflibercept in patients who experience ATEs.

• Wound healing impairment: [U.S. Boxed Warning]: Severely compromised wound healing may occur with ziv-aflibercept/FOLFIRI. Discontinue ziv-aflibercept with compromised wound healing. Withhold ziv-aflibercept at least 4 weeks prior to elective surgery. Do not resume ziv-aflibercept treatment until 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, or tooth extraction), ziv-aflibercept may be resumed or initiated as soon as the surgical wound is fully healed.

Special populations:

• Elderly: Certain adverse events, such as diarrhea, dizziness, weakness, weight loss, and dehydration, occurred at a higher incidence in elderly compared to younger adults; monitor closely during treatment.

Monitoring Parameters

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); monitor for signs/symptoms of hemorrhage or GI perforation; monitor elderly patients closely for diarrhea and/or dehydration. Monitor wounds for healing impairment.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies with doses providing systemic exposure equivalent to ~30% of a human dose. The incidence of fetal malformations increased with increasing doses. Patients (male and female) should use effective contraception during therapy and for at least 3 months following treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, weight loss, diarrhea, lack of appetite, loss of strength and energy, mouth sores, rhinorrhea, change in voice, or skin discoloration. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe dizziness, passing out, burning or numbness feeling, wound healing impairment, angina, shortness of breath, vision changes, blindness, or redness or irritation of palms or soles of feet (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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