Prescription Drug Information: ZALTRAP (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept.

Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were present in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 0.6 times the AUC in patients at the 4 mg per kg dose.

13.2 Animal Toxicology and/or Pharmacology

Repeated administration of ziv-aflibercept resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, ziv-aflibercept administration reduced fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile strength.

14 CLINICAL STUDIES

The efficacy of ZALTRAP was evaluated in VELOUR (NCT00561470), a randomized (1:1), double-blind, placebo-controlled study in patients with mCRC who are resistant to or have progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab. Patients were randomized to receive either ZALTRAP 4 mg per kg intravenously over 1 hour on day 1 or placebo in combination with FOLFIRI (irinotecan 180 mg/m2 intravenously over 90 minutes and leucovorin [dl racemic] 400 mg/m2 intravenously over 2 hours at the same time on day 1 using a Y-line, followed by fluorouracil 400 mg/m2 as an intravenous bolus and then by fluorouracil 2400 mg/m2 as a continuous intravenous infusion over 46 hours). The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. Randomization was stratified by the Eastern Cooperative Oncology Group performance status (PS) (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR).

Demographics characteristics were similar between treatment arms. A total of 1226 patients were randomized, 612 to the ZALTRAP arm and 614 to the placebo arm. The median age was 61 years, 59% were men, 87% were White, 7% were Asian, 3.5% were Black, and 98% had a baseline ECOG PS of 0 or 1. Among the 1226 randomized patients, 89% and 90% of patients treated with placebo/FOLFIRI and ZALTRAP/FOLFIRI, respectively, received prior oxaliplatin-based combination chemotherapy in the metastatic/advanced setting. A total of 346 patients (28%) received bevacizumab in combination with the prior oxaliplatin-based treatment.

Efficacy results are summarized in Figure 1 and Table 2.

Figure 1: Kaplan-Meier Curves of Overall Survival for VELOUR

Figure 1
(click image for full-size original)
Table 2: Main Efficacy Outcome Measures for VELOUR *
ZALTRAP/FOLFIRIN=612Placebo/FOLFIRIN=614
*
PFS (based on tumor assessment by the IRC): Significance threshold is set to 0.0001.
Stratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no)
Overall objective response rate by IRC
Overall Survival
Number of deaths, n (%)403 (65.8%)460 (74.9%)
Median overall survival (95% CI) (months)13.50 (12.52, 14.95)12.06 (11.07, 13.08)
Stratified Hazard ratio (95% CI)0.817 (0.714, 0.935)
Stratified Log-Rank test p-value0.0032
Progression Free Survival (PFS)*
Number of events, n (%)393 (64.2%)454 (73.9%)
Median PFS (95% CI) (months)6.90 (6.51, 7.20)4.67 (4.21, 5.36)
Stratified Hazard ratio (95% CI)0.758 (0.661, 0.869)
Stratified Log-Rank test p-value 0.00007
Overall Response Rate (ORR)
ORR (CR+PR) (95% CI)19.8% (16.4%, 23.2%)11.1% (8.5%, 13.8%)
Stratified Cochran-Mantel-Haenszel test p-value0.0001

Planned subgroup analyses for overall survival based on stratification factors at randomization yielded an HR of 0.86 (95% CI: 0.68, 1.1) in patients who received prior bevacizumab and an HR of 0.79 (95% CI: 0.67, 0.93) in patients without prior bevacizumab exposure.

16 HOW SUPPLIED/STORAGE AND HANDLING

ZALTRAP (ziv-aflibercept) injection is a clear, colorless to pale-yellow solution supplied in single-dose vials with a concentration of 25 mg/mL.

NDC 0024-5840-01: carton containing one single-dose vial of 100 mg/4 mL (25 mg/mL)

NDC 0024-5841-01: carton containing one single-dose vial of 200 mg/8 mL (25 mg/mL)

Store ZALTRAP vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Keep the vials in the original outer carton to protect from light. Discard unused portion.

17 PATIENT COUNSELING INFORMATION

Hemorrhage

  • Inform patients that ZALTRAP can cause severe bleeding and advise patients to contact their health care provider for bleeding or symptoms of bleeding, including lightheadedness [see Warnings and Precautions (5.1)].

Gastrointestinal Perforation and Fistula Formation

  • Advise patients to immediately contact their health care provider for signs and symptoms of gastrointestinal perforation or fistula [see Warnings and Precautions (5.2, 5.4)].

Impaired Wound Healing

  • Advise patients that ZALTRAP may impair wound healing. Instruct patients to discuss any planned surgical procedure (including tooth extractions) with all their healthcare providers. [see Warnings and Precautions (5.3)].

Hypertension

  • Inform patients that ZALTRAP can cause or exacerbate existing hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5)].

Arterial Thromboembolic Events

Proteinuria

Neutropenia and Neutropenic Complications

Diarrhea and Dehydration

Posterior Reversible Leukoencephalopathy Syndrome

  • Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.10)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential:

Lactation

Manufactured by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
U.S. License No. 1752

ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc.

©2020 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL — 100 mg/4 mL Vial Carton

NDC 0024-5840-01

ZALTRAP®
(ziv-aflibercept)
Injection for
Intravenous Infusion

100 mg/4 mL
(25 mg/mL)

For intravenous infusion only.
Not to be administered by
other routes.
Hyperosmotic, must be diluted.

Single-dose vial.Discard unused portion

Rx ONLY

SANOFI

PRINCIPAL DISPLAY PANEL -- 100 mg/4 mL Vial Carton
(click image for full-size original)

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