Dosing and uses of Zaltrap (ziv-aflibercept)
Adult dosage forms and strengths
injection, IV
- 100mg/4mL vial (25mg/mL)
- 200mg/8mL vial (25mg/mL)
Colorectal Cancer
Indicated in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen
4 mg/kg IV infused over 1 hr q2weeks; administer before any component of the FOLFIRI regimen on the day of treatment
Continue until disease progression or unacceptable toxicity occurs
Dosage modification/Treatment Delay
Discontinue
- Severe hemorrhage
- Gastrointestinal perforation
- Compromised wound healing
- Fistula formation
- Hypertensive crisis or hypertensive encephalopathy
- Arterial thromboembolic events
- Nephrotic syndrome or thrombotic microangiopathy (TMA)
- Reversible posterior leukoencephalopathy syndrome (RPLS)
Temporarily suspend dosing
- At least 4 weeks prior to elective surgery
- For recurrent or severe hypertension, until controlled; once resumed, permanently reduce dose to 2 mg/kg
- Proteinuria >2 g/24 hr; resume when proteinuria <2 g/24 hr
- For recurrent proteinuria, suspend therapy until proteinuria <2 g/24 hr and then permanently reduce dose to 2 mg/kg
Renal & Hepatic Impairment
Renal impairment: No dose adjustment required
Hepatic impairment: No dose adjustment required
Pediatric dosage forms and strengths
Safety and efficacy not established
Zaltrap (ziv-aflibercept) adverse (side) effects
>10%
Leukopenia (78%)
Diarrhea (69%)
Neutropenia (67%)
Proteinuria (62%)
Increased AST (62%)
Stomatitis (50%)
Increased ALT (50%)
Thrombocytopenia (48%)
Fatigue (48%)
Hypertension (41%)
Hemorrhage (38%)
Decreased appetite (32%)
Decreased weight (32%)
Epistaxis (28%)
Abdominal pain (27%)
Dysphonia (25%)
Increased serum creatinine (23%)
Headache (22%)
Asthenia (18%)
Dyspnea (12%)
Palmar-Plantar Erythrodysesthesia Syndrome (11%)
1-10%
UTI (9%)
Dehydration (9%)
Oropharyngeal pain (8%)
Rhinorrhea (6%)
Hemorrhoids (6%)
Rectal hemorrhage (5%)
Proctalgia (5%)
Skin hyperpigmentation (8%)
Arterial thromboembolic events (2.6%)
Fistulas (1.5%)
<1%
GI perforation (0.8%)
RPLS (0.5%)
Postmarketing Reports
Osteonecrosis of the jaw
Cardiac failure, ejection fraction decreased
Warnings
Black box warnings
Increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events (eg, severe intracranial hemorrhage, pulmonary hemorrhage/hemoptysis); monitor for signs and symptoms of bleeding, and discontinue if needed; do not administer with severe hemorrhage
Increased risk of GI perforation including fatalities; monitor for signs and symptoms of bleeding, and discontinue if needed
Shown to impair wound healing; suspend therapy for ≥4 weeks prior to elective surgery; resume therapy ≥4 weeks following major surgery or until surgical wound has healed; for minor surgical procedures (eg, tooth extraction, biopsy, central venous access port placement), resume therapy once surgical wound has healed completely; discontinue in patients with compromised wound healing
Contraindications
None
Cautions
May increase hemorrhage risk (see Black box warnings)
May cause GI perforation (see Black box warnings)
May impair wound healing (see Black box warnings)
Increased risk of fistula formation involving GI and non-GI sites; discontinue if fistula develops
Increased risk of Grade 3-4 hypertension; monitor BP q2weeks or more frequently if indicated; treat with appropriate antihypertensive therapy; temporarily suspend if hypertension uncontrolled, and permanently reduce dose to 2 mg/kg for subsequent cycles once blood pressure normalizes; discontinue with hypertensive encephalopathy or hypertensive crisis
Increased risk of arterial thromboembolic events (eg, TIA, CVA, and angina pectoris); discontinue if thromboembolic event occurs
Increased risk of higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection; monitor CBC with differential count at baseline and prior to initiation of each cycle; delay if neutrophil count ≥1.5 x 10^9/L
Increased risk of severe diarrhea, especially in patients aged ≥65 years; monitor closely
Increased risk of RPLS (also known as posterior reversible leukoencephalopathy syndrome); confirm RPLS diagnosis with MRI and discontinue if present; RPLS may resolve or improve within days, but some patients have experienced ongoing neurologic sequelae or death
Proteinuria
- Increased risk of severe proteinuria, nephrotic syndrome and thrombotic microangiopathy (TMA)
- Monitor by urine dipstick analysis and urinary protein creatinine ratio (UPCR)
- Obtain 24-hour urine collection in patients with UPCR ≥1; suspend if proteinuria is ≥2 g/24hr, and resume when ≤2 g/24hr; if reoccurs, suspend until ≤2 g/24hr and permanently reduce dose to 2 mg/kg for subsequent cycles; discontinue in patients who develop TMA or nephrotic syndrome
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown whether distributed in breast milk; because of potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breast feeding or discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Zaltrap (ziv-aflibercept)
Mechanism of action
Recombinant fusion protein; soluble receptor that binds to human VEGF-A, VEGF-B and P1GF; binding to these endogenous ligands leads to inhibition of binding and activation of their cognate receptors, which can result in decreased neovascularization and decreased vascular permeability; in animals, shown to inhibit proliferation of endothelial cells, leading to inhibition of growth of new blood vessels
Distribution
Steady state concentrations reached by second dose
Accumulation ration: 1.2 after administration 4 mg/kg every two weeks
Elimination
Half-life: 6 days (range of 4-7 days)
Administration
IV Preparation
Clear, colorless to pale yellow solution; do not use if solution if discolored or cloudy
Do not re-enter vial after initial puncture; discard unused portion
Withdraw prescribed dose and dilute in 0.9% NaCl or D5W to achieve final concentration of 0.6–8 mg/mL; use PVC infusion bags containing DEHP or polyolefin infusion bags
IV Administration
Administer diluted solution as IV infusion over 1 hr through a 0.2 micron polyethersulfone filter
Do not use filters made of polyvinylidene fluoride (PVDF) or nylon
Do not combine with other drugs in same infusion bag or IV line
Infusion set compatibility: Administer using infusion set of PVC containing DEHP, DEHP free PVC containing TOTM, polypropylene, polyethylene lined PVC, or polyurethane
Do not administer as an IV bolus
Storage
Unopened vials: Refrigerator at 2-8°C (36-46°F); keep in the original outer carton to protect from light
Diluted bags: May refrigerate at 2-8°C (36-46°F) for up to 4 hr; discard unused portion
