ZALTRAP (Page 3 of 5)

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for antiproduct antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.

The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ZALTRAP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and connective tissue disorders: Osteonecrosis of the jaw

Cardiac disorders: Cardiac failure, ejection fraction decreased

7 DRUG INTERACTIONS

No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic interactions were found between ziv-aflibercept and irinotecan/SN-38 or fluorouracil [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)] , ZALTRAP can cause fetal harm when administered to pregnant women. There is insufficient data in pregnant women exposed to ZALTRAP to assess the risks. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal data

In pregnant rabbits, administration of ziv-aflibercept during the period of organogenesis resulted in an increase in postimplantation loss and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and anal atresia), visceral (heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs, supernumerary arches and ribs, and incomplete ossification) at doses greater than or equal to 3 mg per kg, administered once every 3 days (approximately 0.3 times the human exposure at the 4 mg per kg dose based on AUC).

8.2 Lactation

Risk Summary

There are no data on the presence of ziv-aflibercept in human milk, or the effects of ziv-aflibercept on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating ZALTRAP.

Contraception

Based on data from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose.

Infertility

Advise female and male patients of reproductive potential that ZALTRAP may impair reproductive function and fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Safety and efficacy were assessed, but not established in a dose-escalation, safety, and tolerability study (NCT00622414) in 21 patients with solid tumors 2 to 21 years of age (median age 12.9). The mean elimination half-life of free ziv-aflibercept determined after the first dose in 8 pediatric patients aged 5 to 17 years was within the range of values previously observed in adults. The maximum tolerated dose based on body weight in these pediatric patients was lower than the dose known to be safe and effective in adults with mCRC.

Juvenile Animal Toxicity Data

Weekly/every-two-weeks intravenous administration of ziv-aflibercept at dose of 3 mg per kg (approximately 0.6 times the human exposure at the 4 mg per kg dose based on AUC) to growing young adult (sexually mature) cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity (atrophy/loss of the septum and/or turbinates), kidney (glomerulopathy with inflammation), ovary (decreased number of maturing follicles, granulosa cells, and/or theca cells), and adrenal gland (decreased vacuolation with inflammation). In another study in sexually immature cynomolgus monkeys (treated intravenously for 3 months), there were similar effects. The skeletal and nasal cavity effects were not reversible after a post-dosing recovery period.

8.5 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.

8.6 Renal Impairment

No dosage modification is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times upper limit normal [ULN] and any aspartate transaminase [AST]) and moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)]. ZALTRAP has not been studied in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

11 DESCRIPTION

Ziv-aflibercept is a vascular endothelial growth factor inhibitor. It 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 (ziv-aflibercept) injection is a sterile, clear, colorless to pale-yellow, non-pyrogenic, preservative-free, solution for intravenous use. ZALTRAP is supplied in single-dose vials of 100 mg/4 mL and 200 mg/8 mL formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (1 mg/mL), sodium chloride (5.84 mg/mL), sodium citrate (1.45 mg/mL), sodium phosphate (0.8 mg/mL), and sucrose (200 mg/mL), in Water for Injection, USP, at a pH of 6.2.

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