e incidence of antibodies to Zaltrap with the incidence of antibodies to other products may be misleading.
Drug Interactions
No dedicated drug-drug interaction studies have been conducted for Zaltrap. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with Zaltrap in pregnant women. Zaltrap was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. Zaltrap should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose.
Nursing Mothers
It is not known whether Zaltrap is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zaltrap, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the 611 patients with mCRC, patients treated with Zaltrap/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)].
The effect of Zaltrap on overall survival was similar in patients <65 years old and ≥65 years old who received Zaltrap/FOLFIRI.
No dose adjustment of Zaltrap is recommended for patients greater than or equal to 65 years of age.
Hepatic Impairment
No dedicated clinical studies have been conducted to eva luate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.
Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3)]. There are no data available for patients with severe hepatic impairment.
Renal Impairment
No dedicated clinical studies have been conducted to eva luate the eff
