Zaltrap

Zaltrap Adverse Reactions

aflibercept

Manufacturer:

sanofi-aventis

Distributor:

DKSH
Full Prescribing Info
Adverse Reactions
Summary of the Safety Profile: The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP 4 mg/kg every two weeks (one cycle) and 605 patients were treated with placebo/FOLFIRI in a phase III study. Patients received a median number of 9 cycles of the ZALTRAP/FOLFIRI regimen.
The most common adverse reactions (all grades, ≥ 20% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache (see Table 5).
The most common reported grades 3-4 reactions (≥ 5% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 5).
The most frequent adverse reactions leading to permanent discontinuation in ≥ 1% of patients treated with the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8%) including hypertension (2.3%), infections (3.4%), asthenia/fatigue (1.6%, 2.1%), diarrhoea (2.3%), dehydration (1%), stomatitis (1.1%), neutropenia (1.1%), proteinuria (1.5%), and pulmonary embolism (1.1%).
Tabulated Summary of Adverse Reactions: Adverse reactions and laboratory abnormalities reported in patients treated with the ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed in Table 5 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 5 are defined as either any adverse clinical reaction or laboratory abnormality having ≥ 2% greater incidence (all grades) in the aflibercept treatment group in comparison to the placebo treatment group in the MCRC study including those that do not meet this threshold but were consistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of the adverse reactions is graded according to NCI CTC version 3.0 (grade ≥ 3 = G ≥ 3). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies are based on all grades and defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). (See Table 5.)

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In the pivotal MCRC study, anaemia, nausea, vomiting, constipation, alopecia, increased alkaline phosphatase, and hyperbilirubinaemia occurred in ≥ 20% of patients. These were comparable between groups, and the difference between groups did not exceed ≥ 2% incidence for the ZALTRAP/FOLFIRI regimen.
Description of Selected Adverse Reactions: Haemorrhage: Patients treated with ZALTRAP have an increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events. In the pivotal study of MCRC patients, episodes of bleeding/haemorrhage (all grades) was reported in 37.8% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 19.0% of patients treated with the placebo/FOLFIRI regimen. The most common reported form of bleeding was minor (grade 1 - 2) epistaxis occurring in 27.7% of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 3 - 4 haemorrhage including GI haemorrhage, haematuria, and post-procedural haemorrhage was reported in 2.9% of patients receiving the ZALTRAP/FOLFIRI regimen compared with 1.7% of patients receiving the placebo/FOLFIRI regimen. In other studies, severe intracranial haemorrhage and pulmonary haemorrhage/haemoptysis including fatal events have occurred in patients receiving ZALTRAP (see Precautions).
Gastrointestinal Perforation: GI perforation including fatal GI perforation has been reported in patients treated with ZALTRAP. In the pivotal study of MCRC patients, GI perforation (all grades) was reported in 3 of 611 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with the placebo/FOLFIRI regimen. Grade 3-4 GI perforation events occurred in all 3 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and in 2 patients (0.3%) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3 - 4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo (see Precautions).
Fistula Formation: Fistula formation involving GI and non-GI sites has occurred in patients treated with ZALTRAP. In the pivotal study of MCRC patients, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with the placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of fistula (all grades) was 1.1% for patients treated with ZALTRAP and 0.2% for patients treated with placebo. Grade 3 - 4 fistula occurred in 0.2% of patients treated with ZALTRAP and 0.1% of patients treated with placebo (see Precautions).
Hypertension: In the pivotal study of MCRC patients, hypertension (all grades) has been reported in 41.2% of patients treated with ZALTRAP/FOLFIRI and 10.7% of patients treated with placebo/FOLFIRI. An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients receiving the ZALTRAP/FOLFIRI regimen. Grade 3 hypertension (requiring adjustment in existing anti-hypertensive therapy or treatment with more than one medicinal product) was reported in 1.5% of patients treated with the placebo/FOLFIRI regimen and 19.1% of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with the ZALTRAP/FOLFIRI regimen. Among those patients treated with the ZALTRAP/FOLFIRI regimen developing grade 3 - 4 hypertension, 54% had onset during the first two cycles of treatment (see Precautions).
Thrombotic and Embolic Events: Arterial Thromboembolic Events: In the pivotal study of MCRC patients, ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) were reported in 2.6% of patients treated with the ZALTRAP/FOLFIRI regimen and 1.5% of patients treated with the placebo/FOLFIRI regimen. Grade 3 - 4 events occurred in 11 patients (1.8%) treated with the ZALTRAP/FOLFIRI regimen and 3 patients (0.5%) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of ATE (all grades) was 2.3% for patients treated with ZALTRAP and 1.7% for patients treated with placebo. Grade 3 - 4 ATE occurred in 1.7% of patients treated with ZALTRAP and 1.0% of patients treated with placebo (see Precautions).
Venous Thromboembolic Events: Venous thromboembolic events (VTE) include deep venous thrombosis and pulmonary embolism. In the pivotal study of MCRC patients, all grades VTE occurred in 9.3% of patients treated with the ZALTRAP/FOLFIRI regimen and 7.3% of patients treated with the placebo/FOLFIRI regimen. Grade 3 - 4 VTE occurred in 7.9% of patients treated with the ZALTRAP/FOLFIRI regimen and in 6.3% of patients treated with the placebo/FOLFIRI regimen. Pulmonary embolism occurred in 4.6% of patients treated with the ZALTRAP/FOLFIRI regimen and 3.5% of patients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of VTE (all grades) was 7.1% for patients treated with ZALTRAP and 7.1% for patients treated with placebo.
Proteinuria: In the pivotal study of MCRC patients, proteinuria (compiled from clinical and laboratory data) was reported in 62.2% patients treated with the ZALTRAP/FOLFIRI regimen compared to 40.7% patients treated with the placebo/FOLFIRI regimen. Grade 3 - 4 proteinuria occurred in 7.9% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.2% of patients treated with the placebo/FOLFIRI regimen. Nephrotic syndrome occurred in 2 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen compared to none of the patients treated with the placebo/FOLFIRI regimen. One patient treated with the ZALTRAP/FOLFIRI regimen presenting with proteinuria and hypertension was diagnosed with thrombotic microangiopathy (TMA). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of nephrotic syndrome was 0.5% of patients treated with ZALTRAP and 0.1% of patients treated with placebo (see Precautions).
Neutropenia and Neutropenic Complications: In the pivotal study of MCRC patients, neutropenia (all grades) has been reported in 67.8% of patients treated with ZALTRAP/FOLFIRI and 56.3% of patients treated with placebo/FOLFIRI. Grade 3-4 neutropenia was observed in 36.7% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 29.5% patients treated with the placebo/FOLFIRI regimen. The most common grade 3 - 4 neutropenic complication was the occurrence of febrile neutropenia in 4.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.7% of patients treated with the placebo/FOLFIRI regimen. Grade 3 - 4 neutropenic infection/sepsis occurred in 1.5% of patients treated with the ZALTRAP/FOLFIRI regimen and 1.2% of patients treated with the placebo/FOLFIRI regimen (see Precautions).
Infections: Infections occurred at a higher frequency in patients receiving the ZALTRAP/FOLFIRI regimen (46.2%, all grades; 12.3%, grade 3 - 4) than in patients receiving the placebo/FOLFIRI regimen (32.7%, all grades; 6.9%, grade 3 - 4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
Diarrhoea and Dehydration: In the pivotal study of MCRC patients, diarrhoea (all grades) has been observed in 69.2% of patients treated with ZALTRAP/FOLFIRI and 56.5% of patients treated with placebo/FOLFIRI. Dehydration (all grades) has been observed in 9.0% of patients treated with ZALTRAP/FOLFIRI and 3.0% of patients treated with placebo/FOLFIRI. Grade 3-4 diarrhoea was reported in 19.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 7.8% of patients treated with the placebo/FOLFIRI regimen. Grade 3 - 4 dehydration was reported in 4.3% of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.3% of patients treated with the placebo/FOLFIRI regimen (see Precautions).
Hypersensitivity Reactions: In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in 0.3% of patients treated with the ZALTRAP/FOLFIRI regimen and 0.5% of patients treated with the placebo/FOLFIRI regimen (see Precautions).
Compromised Wound Healing: Treatment with ZALTRAP is associated with potential for compromised wound healing (wound dehiscence, anastomotic leakage). In the pivotal study for MCRC, compromised wound healing was reported in 3 patients (0.5%) treated with the ZALTRAP/FOLFIRI regimen and 5 patients (0.8%) treated with the placebo/FOLFIRI regimen. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with the ZALTRAP/FOLFIRI regimen and in none of the patients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of compromised wound healing (all grades) was 0.5% for patients treated with ZALTRAP and 0.4% for patients treated with placebo. Grade 3 - 4 compromised wound healing occurred in 0.2% of patients treated with ZALTRAP and none of patients treated with placebo (see Precautions).
Posterior Reversible Encephalopathy Syndrome (PRES): PRES was not reported in the pivotal Phase III study of MCRC patients. In other studies, PRES was reported in patients treated with monotherapy ZALTRAP (0.5%) and in combination with other chemotherapies (see Precautions).
Additional adverse reactions and laboratory abnormalities reported with a ≥ 5% difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen: The following adverse reactions and laboratory abnormalities were reported with a ≥ 5% difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen (in order of decreasing frequency): leucopenia (78.3% versus 72.4% all grades; 15.6% versus 12.2% Grades 3 - 4), increased AST (57.5% versus 50.2% all grades; 3.1% versus 1.7% Grades 3 - 4), stomatitis (50.1% versus 32.9% all grades; 12.8% versus 4.6% Grades 3 - 4), fatigue (47.8% versus 39.0% all grades; 12.6% versus 7.8% Grade 3 - 4), thrombocytopenia (47.4% versus 33.8% all grades; 3.3% versus 1.7% Grades 3 - 4), increased ALT (47.3% versus 37.1% all grades; 2.7% versus 2.2% Grades 3 - 4), decreased appetite (31.9% versus 23.8% all grades; 3.4% versus 1.8% Grade 3 - 4), weight loss (31.9% versus 14.4% all grades; 2.6% versus 0.8% Grades 3 - 4), dysphonia (25.4% versus 3.3% all grades; 0.5% versus 0 Grades 3 - 4), headache (22.3% versus 8.8% all grades; 1.6% versus 0.3% Grades 3 - 4), asthenia (18.3% versus 13.2% all grades; 5.1% versus 3.0% Grades 3-4), Palmar-Plantar Erythrodysaesthesia syndrome (11.0% versus 4.3% all grades; 2.8% versus 0.5% Grades 3 - 4), and skin hyperpigmentation (8.2% versus 2.8% all grades; 0 versus 0 Grades 3 - 4).
Paediatric Population: The safety in paediatric patients has not been established.
Other Special Populations: Older People: Of the 611 patients treated with the ZALTRAP/FOLFIRI regimen in the pivotal study of MCRC patients, 172 (28.2%) were aged ≥ 65 and < 75 and 33 (5.4%) were age ≥ 75. Older people (≥ 65 years of age) may be more likely to experience adverse reactions. The incidence of diarrhoea, dizziness, asthenia, weight decrease, and dehydration was increased by ≥ 5% in older people patients compared to younger patients. Older people patients should be closely monitored for the development of diarrhoea and potential dehydration (see Precautions).
Renal Impairment: In patients receiving ZALTRAP, the adverse reactions in patients with mild renal impairment at baseline in three Phase III placebo-controlled clinical studies (N = 352) were comparable with those of patients without renal impairment (N = 642). A limited number of patients having moderate/severe renal impairment at baseline (N = 49) were treated with ZALTRAP. In these patients, non-renal events were generally comparable between patients with renal impairment and those without renal impairment, except a > 10% higher incidence in dehydration (all grades) was noted (see Precautions).
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity with ZALTRAP.
Overall across all clinical oncology studies, similar incidence of low titre anti-drug antibody (ADA) responses (post baseline) in the ADA assay were observed in both patients treated with placebo and ZALTRAP (3.3% and 3.8%, respectively). High-titre antibody responses to aflibercept were not detected in any patients. Seventeen (17) patients treated with ZALTRAP (1.6 %) and two (2) placebo-treated patients (0.2%) were also positive in the neutralising antibody assay. In the pivotal study of MCRC patients, positive responses in the ADA assay were observed at higher levels in patients treated with the placebo/FOLFIRI regimen [18/526 (3.4%)] than with the ZALTRAP/FOLFIRI regimen [8/521 (1.5%)]. Positive results in the neutralising antibody assay in the MCRC pivotal study were also higher in patients treated with the placebo/FOLFIRI regimen [2/526 (0.38%)] than with the ZALTRAP/FOLFIRI regimen [1/521 (0.19%)]. There was no observed impact on the pharmacokinetic profile of aflibercept in patients who were positive in the immunogenicity assays.
Given the similar ADA assay results in patients treated with placebo or ZALTRAP, the actual incidence of immunogenicity with ZALTRAP based on these assays is likely to be overestimated.
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 medicinal products, 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.
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