4.1. Therapeutic indications

ZALTRAP in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy is indicated in adults with metastatic colorectal cancer (MCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

4.2. Posology and method of administration

ZALTRAP should be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

Posology

The recommended dose of ZALTRAP, administered as an intravenous infusion over 1 hour, is 4 mg / kg of body weight, followed by the FOLFIRI regimen. This is considered as one treatment cycle.

The FOLFIRI regimen to be used is irinotecan 180 mg/m2 intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m2 intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-fluorouracil (5-FU) 400 mg / m2 intravenous bolus, followed by 5-FU 2400 mg / m2 continuous intravenous infusion over 46 hours.

The treatment cycle is repeated every 2 weeks.

ZALTRAP treatment should be continued until disease progression or unacceptable toxicity occurs.

Dose modification

ZALTRAP should be discontinued for (see section 4.4):

• Severe haemorrhage

• Gastrointestinal (GI) perforation

• Fistula formation

• Hypertension that is not adequately controlled with anti-hypertensive therapy or occurrence of hypertensive crisis or hypertensive encephalopathy

• Cardiac failure and ejection fraction decreased

• Arterial thromboembolic events (ATE)

• Grade 4 venous thromboembolic events (including pulmonary embolism)

• Nephrotic syndrome or thrombotic microangiopathy (TMA)

• Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis) (see sections 4.3 and 4.4)

• Compromised wound healing requiring medical intervention

• Posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome (RPLS))

ZALTRAP should be temporarily suspended for at least 4 weeks prior to elective surgery (see section 4.4).

ZALTRAP/FOLFIRI Treatment delay or dose modification

Neutropenia or thrombocytopenia (see sections 4.4 and 4.8)

Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109/L or platelet count is ≥75 x 109/L.

Febrile neutropenia or neutropenic sepsis

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 ZALTRAP dose to 2 mg/kg could be considered.

The use of granulocyte colony-stimulating factor (G-CSF) may be considered.

Mild to moderate hypersensitivity reactions to ZALTRAP (including flushing, rash, urticaria, and pruritus) (see section 4.4)

The infusion should be temporarily suspended until the reaction resolves. Treatment with corticosteroids and/or antihistamines can be used as clinically indicated.

Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles.

Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis) (see sections 4.3 and 4.4)

ZALTRAP/FOLFIRI should be discontinued and appropriate medical therapy should be administered.

ZALTRAP Treatment delay and dose modification

Hypertension (see section 4.4)

ZALTRAP should be temporarily suspended until hypertension is controlled.

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

Proteinuria (see section 4.4)

ZALTRAP 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.

FOLFIRI Dose modification when used in combination with ZALTRAP

Severe stomatitis and Palmar-Plantar Erythrodysaesthesia syndrome

5-FU bolus should be reduced and the infusion dose reduced by 20 %.

Severe diarrhoea

Irinotecan dose should be reduced by 15-20 %.

If severe diarrhoea recurs on a subsequent cycle, the 5-FU bolus and infusion dose should also be reduced by 20 %.

If severe diarrhoea persists with both dose reductions, FOLFIRI should be discontinued.

Treatment with anti-diarrhoeal medicinal products and rehydration can be used as needed.

For additional toxicities related to irinotecan, 5-FU, or folinic acid, refer to the current respective summary of product characteristics.

Special populations

Elderly

In the pivotal MCRC study, 28.2 % of patients were aged ≥ 65 and < 75 and 5.4 % of patients were aged ≥ 75. No dose adjustments of ZALTRAP is required in the elderly people.

Hepatic impairment

There have been no formal studies with ZALTRAP in patients with hepatic impairment (see section 5.2). Clinical data suggest that no change in aflibercept dose is required in patients with mild to moderate hepatic impairment. There are no data regarding the administration of aflibercept in patients with severe hepatic impairment.

Renal impairment

There have been no formal studies with ZALTRAP in patients with renal impairment (see section 5.2). Clinical data suggest that no change in starting dose is required in patients with mild to moderate renal impairment. There are very limited data in patients with severe renal impairment; therefore, these patients should be treated with caution.

Paediatric population

There is no relevant use of ZALTRAP in the paediatric population for the indication of metastatic colorectal cancer.

Method of administration

ZALTRAP is to be administered only as an intravenous infusion over 1 hour. Due to hyperosmolality (1000 mOsmol/kg) of the ZALTRAP concentrate, undiluted ZALTRAP concentrate must not be administered as an intravenous push or bolus. ZALTRAP must not be administered as an intravitreal injection (see sections 4.3 and 4.4).

Each vial of concentrate for solution for infusion is for single use (single-dose) only.

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, and on infusion sets for administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to aflibercept or to any of the excipients listed in section 6.1.

Ophthalmic / intravitreal use due to hyperosmotic properties of ZALTRAP (see section 4.4).

For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to the current respective summary of product characteristics.

4.4. Special warnings and precautions for use

Haemorrhage

An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has been reported in patients treated with aflibercept (see section 4.8).

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 (see section 4.2).

Thrombocytopenia has been reported in patients treated with the ZALTRAP/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 ZALTRAP/FOLFIRI should be delayed until platelet count is ≥75 x 109 / L (see section 4.2).

Gastrointestinal perforation

GI perforation including fatal GI perforation has been reported in patients treated with aflibercept (see section 4.8).

Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment should be discontinued in patients who experience GI perforation (see section 4.2).

Fistula formation

Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept (see section 4.8).

Aflibercept treatment should be discontinued in patients who develop fistula (see section 4.2).

Hypertension

An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

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 (see section 4.2).

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 ZALTRAP. Patients with NYHA class III or IV congestive heart failure should not be treated with ZALTRAP.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating ZALTRAP, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Cardiac failure and ejection fraction decreased

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

Thrombotic and embolic events

Arterial thromboembolic events (ATE)

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 (see section 4.8).

Aflibercept treatment should be discontinued in patients who experience an ATE (see section 4.2).

Venous thromboembolic events (VTE)

VTE including deep vein thrombosis (DVT) and pulmonary embolism (infrequently fatal) have been reported in patients treated with aflibercept (see section 4.8).

ZALTRAP should be discontinued in patients with life-threatening (Grade 4) thromboembolic events (including pulmonary embolism) (see section 4.2). 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.

Proteinuria

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept (see section 4.8).

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 (see section 4.2).

Neutropenia and neutropenic complications

A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

Monitoring of complete blood count (CBC) with differential count is recommended at baseline and prior to initiation of each cycle of aflibercept. Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109 / L (see section 4.2). Therapeutic use of G-CSF at first occurrence of grade ≥3 neutropenia and secondary prophylaxis may be considered in patients who may be at increased risk for neutropenia complications.

Diarrhoea and dehydration

A higher incidence of severe diarrhoea has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

Dose modification of FOLFIRI regimen (see section 4.2), anti-diarrhoeal medicinal products, and rehydration as needed should be instituted.

Hypersensitivity reactions

In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

In the event of a severe hypersensitivity reaction (including bronchospasm, dyspnoea, angioedema, and anaphylaxis), aflibercept should be discontinued and appropriate medical measures should be administered (see section 4.2).

In the event of a mild to moderate hypersensitivity reaction to ZALTRAP (including flushing, rash, urticaria, and pruritus), aflibercept should be temporarily suspended until the reaction is resolved. Treatment with corticosteroids and/or antihistamines can be initiated as clinically indicated. Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles (see section 4.2). Caution should be used when retreating patients with prior hypersensitivity reactions as recurrent hypersensitivity reactions have been observed in some patients despite prophylaxis, including corticosteroids.

Compromised wound healing

Aflibercept impaired wound healing in animal models (see section 5.3).

Potential for compromised wound healing (wound dehiscence, anastomotic leakage) has been reported with aflibercept (see section 4.8).

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 (see section 4.2).

Osteonecrosis of the jaw (ONJ)

Cases of ONJ have been reported in cancer patients treated with Zaltrap, several of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Zaltrap 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 Zaltrap. Invasive dental procedures should, if possible, be avoided in patients treated with Zaltrap and who have previously received or are receiving intravenous bisphosphonates (see section 4.8).

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 aflibercept as monotherapy and in combination with other chemotherapies (see section 4.8).

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 (see section 4.2).

Elderly

Elderly patients ≥65 years had an increased risk of diarrhoea, dizziness, asthenia, weight loss and dehydration. Careful monitoring is recommended in order to rapidly detect and treat signs and symptoms of diarrhoea and dehydration and to minimize potential risk (see section 4.8).

Renal impairment

There are very limited data available for patients with severe renal impairment treated with aflibercept. No dose adjustment is required for aflibercept (see sections 4.2, 4.8 and 5.2).

Performance status and co-morbidities

Patients with ECOG performance status ≥2 or having significant co-morbidities may be at greater risk for a poor clinical outcome and should be carefully monitored for early clinical deterioration.

Off-label intravitreal use

ZALTRAP is a hyperosmotic solution, which is not formulated for compatibility with the intraocular environment. ZALTRAP must not be administered as an intravitreal injection (see section 4.3).

ZALTRAP contains sodium

This medicinal product contains up to 22 mg sodium per vial, equivalent to 1.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

Population pharmacokinetics analysis and inter study comparisons did not reveal any pharmacokinetic drug-drug interaction between aflibercept and the FOLFIRI regimen.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in females

Women of childbearing potential should be advised to avoid becoming pregnant while on ZALTRAP, and should be informed of the potential hazard to the foetus. Women of childbearing potential treated with ZALTRAP must use effective contraception during treatment and for 3 months after the last dose of treatment.

Pregnancy

There are no data from the use of aflibercept in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As angiogenesis is critical to foetal development, the inhibition of angiogenesis following administration of ZALTRAP may result in adverse effects on pregnancy. ZALTRAP should be used only if the potential benefit justifies the potential risk during pregnancy. If the patient becomes pregnant while taking ZALTRAP, she should be informed of the potential hazard to the foetus.

Breast-feeding

No studies have been conducted to assess the impact of ZALTRAP 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. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ZALTRAP therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Male and female fertility are likely to be compromised during treatment with aflibercept based on studies in monkeys (see section 5.3).

4.7. Effects on ability to drive and use machines

ZALTRAP has no or negligible influence on the ability to drive and use machines. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive or use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1,216 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 1).

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 1).

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 1 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 1 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).

Table 1 - Adverse reactions reported in patients treated with the ZALTRAP/FOLFIRI regimen from the MCRC study

System Organ Class

Frequency Category

Adverse Reaction

All grades

Grades ≥3

Infections and infestations

Very common

Infection (1)

Infection (1)

Common

Neutropenic infection/sepsis (1)

Urinary tract infection

Nasopharyngitis

Neutropenic infection/sepsis (1)

Uncommon

Urinary tract infection

Blood and lymphatic system disorders

Very common

Leucopenia (2)

Neutropenia (1),(2)

Thrombocytopenia (2)

Leucopenia (2)

Neutropenia (2)

Common

Febrile neutropenia

Febrile neutropenia

Thrombocytopenia (2)

Immune system disorders

Common

Hypersensitivity (1)

Uncommon

Hypersensitivity (1)

Metabolism and nutrition disorders

Very common

Decreased appetite

Weight loss

Common

Dehydration (1)

Dehydration (1)

Decreased appetite

Weight loss

Cardiac disorders

Uncommon

Cardiac failure

Rare

Ejection fraction decreased

Nervous system disorders

Very common

Headache

Common

Headache

Uncommon

PRES (1),(4)

PRES (1),(4)

Vascular disorders

Very common

Hypertension (1)

Haemorrhage (1)

Hypertension

Common

Arterial thromboembolism (1)

Venous thromboembolism (1)

Arterial thromboembolism (1)

Venous thromboembolism (1)

Haemorrhage (1)

Not known

Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea

Epistaxis

Dysphonia

Common

Oropharyngeal pain

Rhinorrhoea

Uncommon

Dyspnoea

Epistaxis

Dysphonia

Oropharyngeal pain

Gastrointestinal disorders

Very common

Diarrhoea (1)

Stomatitis

Abdominal pain

Abdominal pain upper

Diarrhoea (1)

Stomatitis

Common

Rectal haemorrhage

Fistula (1)

Aphthous stomatitis

Haemorrhoids

Proctalgia

Toothache

Abdominal pain

Abdominal pain upper

Uncommon

GI perforation (1)

GI perforation (1)

Rectal haemorrhage

Fistula (1)

Aphthous stomatitis

Proctalgia

Hepatobiliary disorders

Very common

Increased AST (2)

Increased ALT (2)

Common

Increased AST (2)

Increased ALT (2)

Skin and subcutaneous tissue disorders

Very common

Palmar-Plantar Erythrodysaesthesia syndrome

Common

Skin hyperpigmentation

Palmar-Plantar Erythrodysaesthesia syndrome

Uncommon

Compromised wound healing (1)

Compromised wound healing (1)

Musculoskeletal and connective tissue disorders

Uncommon

Osteonecrosis of the Jaw (ONJ)

Renal and urinary disorders

Very common

Proteinuria (1),(3)

Increased serum creatinine

Common

Proteinuria (1),(3)

Uncommon

Nephrotic syndrome (1)

Thrombotic microangiopathy (1)

Nephrotic syndrome (1)

Thrombotic microangiopathy (1)

General disorders and administration site conditions

Very common

Asthenic conditions

Asthenic conditions

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 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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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

Elderly

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. 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 (see section 4.4).

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 section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information on the safety of aflibercept given at doses exceeding 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most commonly observed adverse reactions at these doses were similar to those observed at the therapeutic dose.

There is no specific antidote to ZALTRAP overdose. Cases of overdose should be managed by appropriate supportive measures particularly with regard to monitoring and treatment of hypertension and proteinuria. The patient should remain under close medical supervision to monitor any adverse reactions (see section 4.8).