Based on findings from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.1, 8.3)].
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hemorrhage [see Warnings and Precautions (5.1)]
- Gastrointestinal Perforation [see Warnings and Precautions (5.2)]
- Impaired Wound Healing [see Warnings and Precautions (5.3)]
- Fistula Formation [see Warnings and Precautions (5.4)]
- Hypertension [see Warnings and Precautions (5.5)]
- Arterial Thromboembolic Events [see Warnings and Precautions (5.6)]
- Proteinuria [see Warnings and Precautions (5.7)]
- Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)]
- Diarrhea and Dehydration [see Warnings and Precautions (5.9)]
- Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR (EFC102621) [see Clinical Studies (14)]. Patients received ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two weeks (one cycle) in combination with FOLFIRI. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI.
The most common Grade 3–4 adverse reactions (≥5%) in the ZALTRAP/FOLFIRI arm were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
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. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI.
The most common adverse reactions (≥20%) in the ZALTRAP/FOLFIRI arm 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.
Adverse reactions and laboratory abnormalities that occurred in ≥5% (all grades) of patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients who received ZALTRAP/FOLFIRI compared to those who received placebo/FOLFIRI in VELOUR are shown in Table 1. VELOUR was not designed to demonstrate a statistically significant difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to placebo/FOLFIRI for any adverse reactions listed below.
|Primary System Organ ClassPreferred Term||ZALTRAP/ FOLFIRI(N=611)||Placebo/ FOLFIRI(N=605)|
|All grades (%)||Grades 3–4 (%)||All grades (%)||Grades 3–4 (%)|
|Note: Adverse Reactions are reported using MedDRA version 13.1 and graded using NCI CTC version 3.0|
|Blood and lymphatic system disorders|
|Abdominal Pain Upper||11||1||8||1|
|Renal and urinary disorders|
|Serum creatinine increased||23||0||19||0.5|
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Respiratory, thoracic and mediastinal disorders|
|Nervous system disorders|
|Skin and subcutaneous tissue disorders|
|Palmar-Plantar Erythrodysesthesia Syndrome||11||3||4||0.5|
|Urinary Tract Infection||9||0.8||6||0.8|
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.
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