ZALTRAP- aflibercept solution, concentrate
sanofi-aventis U.S. LLC
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING
Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].
Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
1 INDICATIONS AND USAGE
ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) ].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose and Schedule
Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) ].
Continue ZALTRAP until disease progression or unacceptable toxicity.
2.2 Dose Modification/Treatment Delay Recommendations
Discontinue ZALTRAP for:
Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)]
Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)]
Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)]
Fistula formation [see Warnings and Precautions (5.4) ]
Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5) ]
Arterial thromboembolic events [see Warnings and Precautions (5.6) ]
Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7) ]
Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10) ]
Temporarily suspend ZALTRAP:
At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3) ]
For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5) ].
For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7) ].
For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.
2.3 Preparation for Administration
Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles.
Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial.
Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL.
Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.
Store diluted ZALTRAP at 2°–8°C (36°–46°F) for up to 24 hours, or at controlled room temperature 20°–25°C (68°–77°F) for up to 8 hours. Discard any unused portion left in the infusion bag.
Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.
Do not administer as an intravenous (IV) push or bolus.
Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line.
Administer ZALTRAP using an infusion set made of one of the following materials:
PVC containing DEHP
DEHP free PVC containing trioctyl-trimellitate (TOTM)
polyethylene lined PVC
3 DOSAGE FORMS AND STRENGTHS
ZALTRAP is available as:
100 mg per 4 mL (25 mg per mL) solution, single-use vial
200 mg per 8 mL (25 mg per mL) solution, single-use vial
Ziv-aflibercept is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgG1. Ziv-aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Ziv-aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
ZALTRAP is a sterile, clear, colorless to pale yellow, non-pyrogenic, preservative-free, solution for administration by intravenous infusion. ZALTRAP is supplied in single-use vials of 100 mg per 4 ml and 200 mg per 8 ml formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (0.1%), sodium chloride (100 mM), sodium citrate (5 mM), sodium phosphate (5 mM), and sucrose (20%), in Water for Injection USP, at a pH of 6.2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ziv-aflibercept acts as a soluble receptor that binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121 ), to human VEGF-B (KD of 1.92 pM), and to human PlGF (KD of 39 pM for PlGF-2). By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.
In animals, ziv-aflibercept was shown to inhibit the proliferation of endothelial cells, thereby inhibiting the growth of new blood vessels. Ziv-aflibercept inhibited the growth of xenotransplanted colon tumors in mice.