Aflibercept

Cardiac failure and ejection fraction decreased have been reported in patients treated with aflibercept. Baseline and periodic evaluations of left ventricular function should be considered while the patient is receiving aflibercept. Patients should be monitored for signs and symptoms of cardiac failure and ejection fraction decreased. Discontinue aflibercept in patients who experience cardiac failure and ejection fraction decreased.

An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has been reported in patients treated with aflibercept.

Patients should be monitored for signs and symptoms of GI bleeding and other severe bleeding. Aflibercept should not be administered to patients with severe haemorrhage.

Thrombocytopenia has been reported in patients treated with the aflibercept/FOLFIRI regimen. Monitoring of complete blood count (CBC) with platelets is recommended at baseline, prior to initiation of each cycle of aflibercept, and as clinically necessary. Administration of the aflibercept/FOLFIRI should be delayed until platelet count is >75 × 10⁹/L.

Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility. Such effects are not expected after ocular administration with very low systemic exposure.

Administration of aflibercept/FOLFIRI should be delayed until neutrophil count is >1.5 × 10⁹/L.

Arterial thromboembolic events (ATE) (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) have been observed in patients treated with aflibercept. Aflibercept treatment should be discontinued in patients who experience an ATE.

Aflibercept impaired wound healing in animal models. Potential for compromised wound healing (wound dehiscence, anastomotic leakage) has been reported with aflibercept. Aflibercept should be suspended for at least 4 weeks prior to elective surgery.

It is recommended that aflibercept not be initiated for at least 4 weeks following major surgery and not until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, aflibercept may be initiated/restarted once the surgical wound is fully healed. Aflibercept should be discontinued in patients with compromised wound healing requiring medical intervention.

Aflibercept should be suspended when proteinuria ≥2 grams per 24 hours and resumed when proteinuria <2 grams per 24 hours.

If recurrence, the treatment should be suspended until <2 grams per 24 hours and then the dose reduces to 2 mg/kg.

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept. Proteinuria should be monitored by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria before each aflibercept administration. Patients with a dipstick of ≥2+ for protein or a UPCR >1 or a protein/creatinine ratio (PCR)> 100 mg/mmol should undergo a 24-hour urine collection. Aflibercept administration should be suspended for ≥2 grams of proteinuria/24 hours and restarted when proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be suspended until <2 grams/24 hours and then the dose reduced to 2 mg/kg. Aflibercept treatment should be discontinued in patients who develop nephrotic syndrome or TMA.

Administration of aflibercept/FOLFIRI should be delayed until neutrophil count is platelet count is >75 × 10⁹/L.

Aflibercept should be temporarily suspended until hypertension is controlled. In case of recurrent medically significant or severe hypertension, despite optimal treatment, aflibercept should be suspended until the hypertension is controlled and the dose reduced to 2 mg/kg for subsequent cycles.

An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients treated with the aflibercept/FOLFIRI regimen.

Pre-existing hypertension must be adequately controlled before starting aflibercept. If hypertension cannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommended to monitor blood pressure every two weeks, including before each administration or as clinically indicated during treatment with aflibercept. In the event of hypertension on aflibercept treatment, blood pressure should be controlled with appropriate anti-hypertensive therapy and blood pressure should be monitored regularly. In case of recurrent medically significant or severe hypertension, despite optimal treatment, aflibercept should be suspended until the hypertension is controlled and the aflibercept dose should be reduced to 2 mg/kg for subsequent cycles. Aflibercept should be permanently discontinued if hypertension cannot be adequately managed with appropriate anti-hypertensive therapy or aflibercept dose reduction, or if hypertensive crisis or hypertensive encephalopathy occurs.

Hypertension may exacerbate underlying cardiovascular disease. Caution should be exercised when treating patients with history of clinically significant cardiovascular disease such as coronary artery disease, or congestive heart failure with aflibercept. Patients with NYHA class III or IV congestive heart failure should not be treated with aflibercept.

Irinotecan dose should be reduced by 15-20 % in subsequent cycles. If recurrence, 5-FU bolus and infusion doses should additionally be reduced by 20% in subsequent cycles. If recurrence after irinotecan and 5-FU dose reductions, reduction of aflibercept dose to 2 mg/kg could be considered. The use of granulocyte colony-stimulating factor (G-CSF) may be considered.

VTE including deep vein thrombosis (DVT) and pulmonary embolism (infrequently fatal) have been reported in patients treated with aflibercept.

Aflibercept should be discontinued in patients with life-threatening (Grade 4) thromboembolic events (including pulmonary embolism). Patients with Grade 3 DVT should be treated with anticoagulation as clinically indicated, and aflibercept therapy should be continued. In the event of recurrence, despite appropriate anticoagulation, aflibercept treatment should be discontinued. Patients with thromboembolic events of Grade 3 or lower need to be closely monitored.

Cases of ONJ have been reported in cancer patients treated with aflibercept, several of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when aflibercept and intravenous bisphosphonates are administered concurrently or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with aflibercept. Invasive dental procedures should, if possible, be avoided in patients treated with aflibercept and who have previously received or are receiving intravenous bisphosphonates.

Posterior reversible encephalopathy syndrome (PRES) was not reported in the pivotal phase III study of MCRC patients. In other studies, PRES was reported in patients treated with aflibercept as monotherapy and in combination with other chemotherapies. PRES may present with altered mental status, seizure, nausea, vomiting, headache, or visual disturbances. The diagnosis of PRES is confirmed by brain Magnetic Resonance Imaging (MRI). Aflibercept should be discontinued in patients that develop PRES.

Gastrointestinal perforation including fatal GI perforation has been reported in patients treated with aflibercept.

Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment should be discontinued in patients who experience GI perforation.

Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept. Aflibercept treatment should be discontinued in patients who develop fistula.

There are no data on the use of aflibercept in pregnant women. Studies in animals have shown embryo-foetal toxicity.

As angiogenesis is critical to foetal development, the inhibition of angiogenesis following administration of aflibercept may result in adverse effects on pregnancy. Aflibercept should be used only if the potential benefit justifies the potential risk during pregnancy. If the patient becomes pregnant while taking aflibercept, she should be informed of the potential hazard to the foetus.

No studies have been conducted to assess the impact of aflibercept on milk production, its presence in breast milk or its effects on the breast-fed child.

It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded.

Aflibercept is not recommended during breast-feeding. A decision must be made whether to discontinue breast-feeding or to abstain from aflibercept therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility. Such effects are not expected after ocular administration with very low systemic exposure.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while on aflibercept, and should be informed of the potential hazard to the foetus. Women of childbearing potential and fertile males should use effective contraception during and up to a minimum of 6 months after the last dose of treatment.

Injection with aflibercept has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances associated either with the injection or the eye examination. Patients should not drive or use machines until their visual function has recovered sufficiently.

h2 ®. Intravitreal administration

Summary of the safety profile

A total of 3,102 patients constituted the safety population in the eight phase III studies. Among those, 2,501 patients were treated with the recommended dose of 2 mg.

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in less than 1 in 1,900 intravitreal injections with aflibercept and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocular pressure increased.

The most frequently observed adverse reactions (in at least 5% of patients treated with aflibercept) were conjunctival haemorrhage (25%), visual acuity reduced (11%), eye pain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).

List of adverse reactions

The safety data described below include all adverse reactions from the eight phase III studies in the indications wet AMD, CRVO, BRVO, DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

The adverse reactions are listed by system organ class and frequency using the following convention: 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). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic CNV) or during post-marketing surveillance:

Immune system disorders

Uncommon: Hypersensitivity***

Eye disorders

Very common: Visual acuity reduced, Conjunctival haemorrhage, Eye pain

Common: Retinal pigment epithelial tear*, Detachment of the retinal pigment epithelium, Retinal degeneration, Vitreous haemorrhage, Cataract, Cataract cortical, Cataract nuclear, Cataract subcapsular, Corneal erosion, Corneal abrasion, Intraocular pressure increased, Vision blurred, Vitreous floaters, Vitreous detachment, Injection site pain, Foreign body sensation in eyes, Lacrimation increased, Eyelid oedema, Injection site haemorrhage, Punctate keratitis, Conjunctival hyperaemia, Ocular hyperaemia

Uncommon: Endophthalmitis**, Retinal detachment, Retinal tear, Iritis, Uveitis, Iridocyclitis, Lenticular opacities, Corneal epithelium defect, Injection site irritation, Abnormal sensation in eye, Eyelid irritation, Anterior chamber flare, Corneal oedema

Rare: Blindness, Cataract traumatic, Vitritis, Hypopyon

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.
** Culture positive and culture negative endophthalmitis
*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions.

Description of selected adverse reactions

In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage in patients receiving anti-thrombotic agents. This increased incidence was comparable between patients treated with ranibizumab and aflibercept.

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors.

A low incidence rate of arterial thromboembolic events was observed in the aflibercept clinical trials in patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between the groups treated with aflibercept and the respective comparator groups were observed.

As with all therapeutic proteins, there is a potential for immunogenicity with aflibercept.

h2 ®. IV administration

Summary of the safety profile

The safety of aflibercept in combination with FOLFIRI was evaluated in 1,216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with aflibercept 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 aflibercept/FOLFIRI regimen.

The most common adverse reactions (all grades, ≥20% incidence) reported at least 2% greater incidence for the aflibercept/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.

The most common reported grades 3-4 reactions (≥5% incidence) reported at least 2% greater incidence for the aflibercept/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia.

The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with the aflibercept/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%).

Summary of adverse reactions

Adverse reactions and laboratory abnormalities reported in patients treated with the aflibercept/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed below according to MedDRA system organ class and frequency categories. Adverse reactions 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).

Adverse reactions reported in patients treated with the aflibercept/FOLFIRI regimen from the MCRC study:

Note: Adverse reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0
¹ See “Description of selected adverse reactions” in this section
² Based on laboratory values (percentages done on patients with laboratory assessments)
³ Compilation of clinical and laboratory data
⁴ Not reported in MCRC study; however, PRES was reported in patients from other studies treated with aflibercept as monotherapy and in combination with chemotherapies other than FOLFIRI

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 aflibercept/FOLFIRI regimen.

Description of selected adverse reactions

Haemorrhage

Patients treated with aflibercept 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 aflibercept/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 aflibercept/FOLFIRI regimen. Grade 3-4 haemorrhage including GI haemorrhage, haematuria, and post-procedural haemorrhage was reported in 2.9% of patients receiving the aflibercept/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 aflibercept.

Gastrointestinal perforation

GI perforation including fatal GI perforation has been reported in patients treated with aflibercept. In the pivotal study of MCRC patients, GI perforation (all grades) was reported in 3 of 611 patients (0.5%) treated with the aflibercept/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 aflibercept/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 aflibercept and 0.3% for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8% of patients treated with aflibercept and 0.2% of patients treated with placebo.

Fistula formation

Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept. 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 aflibercept/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 aflibercept (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 aflibercept and 0.2% for patients treated with placebo. Grade 3-4 fistula occurred in 0.2% of patients treated with aflibercept and 0.1% of patients treated with placebo.

Hypertension

In the pivotal study of MCRC patients, hypertension (all grades) has been reported in 41.2% of patients treated with aflibercept/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 aflibercept/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 aflibercept/FOLFIRI regimen. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with the aflibercept/FOLFIRI regimen. Among those patients treated with the aflibercept/FOLFIRI regimen developing grade 3-4 hypertension, 54% had onset during the first two cycles of treatment.

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 aflibercept/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 aflibercept/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 aflibercept and 1.7% for patients treated with placebo. Grade 3-4 ATE occurred in 1.7% of patients treated with aflibercept and 1.0% of patients treated with placebo.

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 aflibercept/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 aflibercept/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 aflibercept/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 aflibercept 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 aflibercept/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 aflibercept/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 aflibercept/FOLFIRI regimen compared to none of the patients treated with the placebo/FOLFIRI regimen. One patient treated with the aflibercept/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 aflibercept and 0.1% of patients treated with placebo.

Neutropenia and neutropenic complications

In the pivotal study of MCRC patients, neutropenia (all grades) has been reported in 67.8% of patients treated with aflibercept/FOLFIRI and 56.3% of patients treated with placebo/FOLFIRI. Grade 3-4 neutropenia was observed in 36.7% of patients treated with the aflibercept/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 aflibercept/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 aflibercept/FOLFIRI regimen and 1.2% of patients treated with the placebo/FOLFIRI regimen.

Infections

Infections occurred at a higher frequency in patients receiving the aflibercept/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 aflibercept/FOLFIRI and 56.5% of patients treated with placebo/FOLFIRI. Dehydration (all grades) has been observed in 9.0% of patients treated with aflibercept/FOLFIRI and 3.0% of patients treated with placebo/FOLFIRI. Grade 3-4 diarrhoea was reported in 19.3% of patients treated with the aflibercept/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 aflibercept/FOLFIRI regimen compared to 1.3% of patients treated with the placebo/FOLFIRI regimen.

Hypersensitivity reactions

In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in 0.3% of patients treated with the aflibercept/FOLFIRI regimen and 0.5% of patients treated with the placebo/FOLFIRI regimen.

Compromised wound healing

Treatment with aflibercept 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 aflibercept/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 aflibercept/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 aflibercept and 0.4% for patients treated with placebo. Grade 3-4 compromised wound healing occurred in 0.2% of patients treated with aflibercept and none of patients treated with placebo.

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 aflibercept (0.5%) and in combination with other chemotherapies.

Additional adverse reactions and laboratory abnormalities reported with a ≥5% difference (all grades) in patients treated with the aflibercept/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 aflibercept/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

Elderly

Of the 611 patients treated with the aflibercept/FOLFIRI regimen in the pivotal study of MCRC patients, 172 (28.2%) were aged ≥65 and <75 and 33 (5.4%) were age ≥75. Elderly (≥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 elderly compared to younger patients. Elderly people should be closely monitored for the development of diarrhoea and potential dehydration.

Renal impairment

In patients receiving aflibercept, 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 aflibercept. 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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with aflibercept.

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 aflibercept (3.3% and 3.8%, respectively). High-titre antibody responses to aflibercept were not detected in any patients. Seventeen (17) patients treated with aflibercept (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 aflibercept/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 aflibercept/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 aflibercept, the actual incidence of immunogenicity with aflibercept 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 aflibercept with the incidence of antibodies to other products may be misleading.