Prescription Drug Information: ZALTRAP (Page 2 of 5)

5.11 Embryo-Fetal Toxicity

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)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

6.1 Clinical Trials Experience

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.

Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR
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
*
Compilation of clinical and laboratory data
Blood and lymphatic system disorders
Leukopenia 78 16 72 12
Neutropenia 67 37 57 30
Thrombocytopenia 48 3 35 2
Gastrointestinal disorders
Diarrhea 69 19 57 8
Stomatitis 50 13 33 5
Abdominal Pain 27 4 24 2
Abdominal Pain Upper 11 1 8 1
Hemorrhoids 6 0 2 0
Rectal Hemorrhage 5 0.7 2 0.5
Proctalgia 5 0.3 2 0.3
Investigations
AST increased 62 3 54 2
ALT increased 50 3 39 2
Weight decreased 32 3 14 0.8
Renal and urinary disorders
Proteinuria * 62 8 41 1
Serum creatinine increased 23 0 19 0.5
General disorders and administration site conditions
Fatigue 48 13 39 8
Asthenia 18 5 13 3
Vascular disorders
Hypertension 41 19 11 1.5
Metabolism and nutrition disorders
Decreased Appetite 32 3 24 2
Dehydration 9 4 3 1
Respiratory, thoracic and mediastinal disorders
Epistaxis 28 0.2 7 0
Dysphonia 25 0.5 3 0
Dyspnea 12 0.8 9 0.8
Oropharyngeal Pain 8 0.2 3 0
Rhinorrhea 6 0 2 0
Nervous system disorders
Headache 22 2 9 0.3
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysesthesia Syndrome 11 3 4 0.5
Skin Hyperpigmentation 8 0 3 0
Infections
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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