The following serious adverse reactions are discussed elsewhere in the labeling:
- Hemorrhage [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Gastrointestinal Perforation [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Compromised Wound Healing [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Fistula Formation [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
- Proteinuria [see WARNINGS AND PRECAUTIONS]
- Neutropenia and Neutropenic Complications [see WARNINGS AND PRECAUTIONS]
- Diarrhea and Dehydration [see WARNINGS AND PRECAUTIONS]
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS AND PRECAUTIONS]
Clinical Trial Experience
Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI.
The most common adverse reactions (all grades, ≥ 20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1).
The most common Grade 3-4 adverse reactions ( ≥ 5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).
The most frequent adverse reactions leading to permanent discontinuation in ≥ 1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.
The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays > 7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI.
The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥ 5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥ 2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1.
Table 1: Selected Adverse Reactions and Laboratory Findings in Study 1
|Primary System Organ Class Preferred Term (%)||Placebo/ FOLFIRI
|All grades||Grades 3-4||All grades||Grades 3|
|Infections and infestations|
|Urinary Tract Infection||6%||0.8%||9%||0.8%|
|Blood and lymphatic system disorders|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorders|
|Abdominal Pain Upper||8%||1%||11%||1%|
|Skin and subcutaneous tissue disorders|
|Palmar-Plantar Erythrodysesthesia Syndrome||4%||0.5%||11%||3%|
|Renal and urinary disorders|
|Serum creatinine increased||19%||0.5%||23%||0|
|General disorders and administration site conditions|
|Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0
* Compilation of clinical and laboratory data
Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).
In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3-4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.
As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product 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.
Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading.