Ziv-Aflibercept (Systemic)

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)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

~6 days (range: 4 to 7 days)

Use in Specific Populations

Special Populations Note

Body weight: Patients weighing ≥100 kg 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]) that is resistant to or has progressed on an oxaliplatin-based regimen.

Use: Off Label

Ascites (symptomatic; due to malignant ovarian cancer)c

Data from a multicenter, double-blind, placebo-controlled, parallel group, phase 2 trial in patients with advanced chemoresistant ovarian cancer (including fallopian tube or primary peritoneal adenocarcinoma) and recurrent symptomatic malignant ascites (requiring paracenteses) suggest that ziv-aflibercept may be efficacious in managing refractory ascites and providing symptomatic relief, although vascular endothelial growth factor (VEGF) blockade should be used with caution in this patient population due to the risk of fatal GI perforation (Gotlieb 2012).

Contraindications

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

Dosage and Administration

Dosing: Adult

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 (Gotlieb 2012). 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 (Van Cutsem 2012).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

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:

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.

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 infusion bags. After initial vial puncture, do not re-enter 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.

Storage

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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. 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. Consider therapy modification

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

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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%, postmarketing, and/or case reports: Osteonecrosis of the jaw, reduced ejection fraction, thrombotic thrombocytopenic purpura, wound healing impairment

Warnings/Precautions

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.
• Gastrointestinal perforation: [US Boxed Warning]: 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. [US Boxed Warning]: 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: [US Boxed Warning]: 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: 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.

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). Evaluate pregnancy status prior to use in females of reproductive potential. Monitor for signs/symptoms of hemorrhage or GI perforation; monitor elderly patients closely for diarrhea and/or dehydration. Monitor wounds for healing impairment.

Pregnancy

Pregnancy Considerations

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).

Verify pregnancy status in females of reproductive potential prior to initiating ziv-aflibercept. Females of reproductive potential should use effective contraception during therapy and for 1 month following the last ziv-aflibercept dose. Ziv-aflibercept may impair reproductive function in males and females of reproductive potential.

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 weight loss, diarrhea, lack of appetite, loss of strength and energy, mouth sores, mouth irritation, 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 severe or persistent bleeding), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe headache, severe dizziness, passing out, wound healing impairment, chest pain, shortness of breath, vision changes, severe abdominal pain, 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 health care 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.