ZALTRAP 25mg / ml perfusive solution concentrate medication leaflet

ZALTRAP 25 mg/ml concentrate for solution for infusion

One ml of concentrate for solution for infusion contains 25 mg aflibercept*.

One vial of 4 ml of concentrate contains 100 mg of aflibercept.

One vial of 8 ml of concentrate contains 200 mg of aflibercept.

* Aflibercept is produced in a Chinese hamster ovary (CHO) K-1 mammalian expression system byrecombinant DNA technology.

Each 4 ml vial contains 0.484 mmol of sodium, which is 11.118 mg of sodium, and 8 ml vial contains0.967 mmol of sodium, which is 22.236 mg of sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a clear colourless to pale yellow solution.

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

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

The recommended dose of ZALTRAP, administered as an intravenous infusion over 1 hour, is4 mg/kg of body weight, followed by the FOLFIRI regimen. This is considered as one treatmentcycle.

The FOLFIRI regimen to be used is irinotecan 180 mg/m2 intravenous infusion over 90 minutes andfolinic acid (dl racemic) 400 mg/m² intravenous infusion over 2 hours at the same time on day 1 usinga Y-line, followed by 5-fluorouracil (5-FU) 400 mg/m² intravenous bolus, followed by 5-FU2400 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.

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 ofhypertensive 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, andanaphylaxis) (see sections 4.3 and 4.4)

* Compromised wound healing requiring medical intervention

* Posterior reversible encephalopathy syndrome (PRES) (also known as reversible posteriorleukoencephalopathy syndrome (RPLS))

ZALTRAP should be temporarily suspended for at least 4 weeks prior to elective surgery (see section4.4).

ZALTRAP/FOLFIRI Treatment delay or dose modification

Neutropenia or thrombocytopenia Administration of ZALTRAP/FOLFIRI should be delayed(see sections 4.4 and 4.8) until neutrophil count is ≥1.5 x 109/L or platelet countis ≥75 x 109 /L.

Febrile neutropenia or neutropenic Irinotecan dose should be reduced by 15-20 % insepsis subsequent cycles.

If recurrence, 5-FU bolus and infusion doses shouldadditionally 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 beconsidered.

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

Mild to moderate hypersensitivity The infusion should be temporarily suspended until thereactions to ZALTRAP (including reaction resolves. Treatment with corticosteroids and/orflushing, rash, urticaria, and pruritus) antihistamines can be used as clinically indicated.(see section 4.4)

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

Severe hypersensitivity reactions ZALTRAP/FOLFIRI should be discontinued and(including bronchospasm, dyspnoea, appropriate medical therapy should be administered.angioedema, and anaphylaxis)(see sections 4.3 and 4.4)

ZALTRAP Treatment delay and dose modification

Hypertension ZALTRAP should be temporarily suspended until(see section 4.4) hypertension is controlled.

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

Proteinuria ZALTRAP should be suspended when proteinuria(see section 4.4) ≥2 grams per 24 hours and resumed when proteinuria< 2 grams per 24 hours.

If recurrence, the treatment should be suspendeduntil <2 grams per 24 hours and then the dose reduces to2 mg/kg.

FOLFIRI Dose modification when used in combination with ZALTRAP

Severe stomatitis and Palmar-Plantar 5-FU bolus should be reduced and the infusion dose

Erythrodysaesthesia syndrome reduced by 20 %.

Severe diarrhoea Irinotecan dose should be reduced by 15-20 %.

If severe diarrhoea recurs on a subsequent cycle, the 5-FUbolus 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 andrehydration can be used as needed.

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

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

There have been no formal studies with ZALTRAP in patients with hepatic impairment (see section5.2). Clinical data suggest that no change in aflibercept dose is required in patients with mild tomoderate hepatic impairment. There are no data regarding the administration of aflibercept in patientswith severe hepatic 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 renalimpairment. There are very limited data in patients with severe renal impairment; therefore, thesepatients should be treated with caution.

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

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 beadministered as an intravenous push or bolus. ZALTRAP must not be administered as an intravitrealinjection (see sections 4.3 and 4.4).

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

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

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 thecurrent respective summary of product characteristics.

An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has beenreported 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 toinitiation 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 (seesection 4.8).

Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment shouldbe 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 (seesection 4.8).

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

An increased risk of grade 3-4 hypertension (including hypertension and one case of essentialhypertension) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section4.8).

Pre-existing hypertension must be adequately controlled before starting aflibercept. If hypertensioncannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommendedto monitor blood pressure every two weeks, including before each administration or as clinicallyindicated during treatment with aflibercept. In the event of hypertension on aflibercept treatment,blood pressure should be controlled with appropriate anti-hypertensive therapy and blood pressureshould 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 theaflibercept dose should be reduced to 2 mg/kg for subsequent cycles. Aflibercept should bepermanently discontinued if hypertension cannot be adequately managed with appropriateanti-hypertensive therapy or aflibercept dose reduction, or if hypertensive crisis or hypertensiveencephalopathy occurs (see section 4.2).

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

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating ZALTRAP, this risk should becarefully 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 isreceiving Zaltrap. Patients should be monitored for signs and symptoms of cardiac failure and ejectionfraction decreased. Discontinue ZALTRAP in patients who experience cardiac failure and ejectionfraction decreased.

Thrombotic and embolic events

Arterial thromboembolic events (ATE)

ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiacthrombus, myocardial infarction, arterial embolism, and ischaemic colitis) have been observed inpatients 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 beenreported 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 withanticoagulation as clinically indicated, and aflibercept therapy should be continued. In the event ofrecurrence, despite appropriate anticoagulation, aflibercept treatment should be discontinued. Patientswith thromboembolic events of Grade 3 or lower need to be closely monitored.

Proteinuria

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observedin 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 restartedwhen proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be suspendeduntil <2 grams/24 hours and then the dose reduced to 2 mg/kg. Aflibercept treatment should bediscontinued 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) hasbeen 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 andprior to initiation of each cycle of aflibercept. Administration of ZALTRAP/FOLFIRI should bedelayed until neutrophil count is ≥1.5 x 109/L (see section 4.2). Therapeutic use of G-CSF at firstoccurrence of grade ≥ 3 neutropenia and secondary prophylaxis may be considered in patients whomay 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, andrehydration as needed should be instituted.

In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in patientstreated 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 beadministered (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 (seesection 4.2). Caution should be used when retreating patients with prior hypersensitivity reactions asrecurrent 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 reportedwith 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 notuntil the surgical wound is fully healed. For minor surgery such as central venous access portplacement, biopsy, and tooth extraction, aflibercept may be initiated/restarted once the surgical woundis fully healed. Aflibercept should be discontinued in patients with compromised wound healingrequiring medical intervention (see section 4.2).

Cases of ONJ have been reported in cancer patients treated with Zaltrap, several of whom hadreceived prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is anidentified risk. Caution should be exercised when Zaltrap and intravenous bisphosphonates areadministered concurrently or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriatepreventive dentistry should be considered prior to starting the treatment with Zaltrap. Invasive dentalprocedures should, if possible, be avoided in patients treated with Zaltrap and who have previouslyreceived 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 wasreported in patients treated with aflibercept as monotherapy and in combination with otherchemotherapies (see section 4.8).

PRES may present with altered mental status, seizure, nausea, vomiting, headache, or visualdisturbances. 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 patients ≥65 years had an increased risk of diarrhoea, dizziness, asthenia, weight loss anddehydration. Careful monitoring is recommended in order to rapidly detect and treat signs andsymptoms of diarrhoea and dehydration and to minimize potential risk (see section 4.8).

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, pct. 4.8 and 5.2).

Performance status and co-morbidities

Patients with ECOG performance status ≥ 2 or having significant co-morbidities may be at greaterrisk 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 intraocularenvironment. 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 WHOrecommended maximum daily intake of 2 g sodium for an adult.

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

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

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 treatedwith ZALTRAP must use effective contraception during treatment and for 3 months after the last doseof treatment.

There are no data from the use of aflibercept in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). As angiogenesis is critical to foetal development, the inhibitionof 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. Ifthe patient becomes pregnant while taking ZALTRAP, she should be informed of the potential hazardto the foetus.

No studies have been conducted to assess the impact of ZALTRAP on milk production, its presence inbreast 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 beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom ZALTRAP therapy taking into account the benefit of breast-feeding for the child and the benefitof therapy for the woman.

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

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

The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1,216 patients previouslytreated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP4 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 % greaterincidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in orderof decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartateaminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase(ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increasedserum creatinine, and headache (see Table 1).

The most common reported grades 3-4 reactions ( ≥5 % incidence) reported at least 2 % greaterincidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in orderof 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 treatedwith the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8 %) includinghypertension (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 pulmonaryembolism (1.1 %).

Adverse reactions and laboratory abnormalities reported in patients treated with the

ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen arelisted in Table 1 according to MedDRA system organ class and frequency categories. Adversereactions in Table 1 are defined as either any adverse clinical reaction or laboratory abnormalityhaving ≥ 2 % greater incidence (all grades) in the aflibercept treatment group in comparison to theplacebo treatment group in the MCRC study including those that do not meet this threshold but wereconsistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of theadverse reactions is graded according to NCI CTC version 3.0 (grade ≥ 3 = G ≥ 3). Within eachfrequency 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); notknown (cannot be estimated from the available data).

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

System Organ Class Adverse Reaction

Frequency Category All grades Grades ≥3

Very common Infection (1) Infection (1)

Common Neutropenic infection/sepsis (1) Neutropenic infection/sepsis (1)

Nasopharyngitis

Uncommon Urinary tract infection

Very common Leucopenia (2) Leucopenia (2)

Neutropenia (1),(2) Neutropenia (2)

Thrombocytopenia (2)

Common Febrile neutropenia Febrile neutropenia

Thrombocytopenia (2)

Common Hypersensitivity (1)

Uncommon Hypersensitivity (1)

Very common Decreased appetite

Weight loss

Common Dehydration (1) Dehydration (1)

Decreased appetite

Weight loss

Uncommon Cardiac failure

Rare Ejection fraction decreased

Very common Headache

Common Headache

Uncommon PRES (1),(4) PRES (1),(4)

Very common Hypertension (1) Hypertension

Haemorrhage (1)

System Organ Class Adverse Reaction

Frequency Category All grades Grades ≥3

Common Arterial thromboembolism (1) Arterial thromboembolism (1)

Venous thromboembolism (1) Venous thromboembolism (1)

Haemorrhage (1)

Not known Aneurysms and artery dissections

Very common Dyspnoea

Epistaxis

Dysphonia

Common Oropharyngeal pain

Rhinorrhoea

Uncommon Dyspnoea

Epistaxis

Dysphonia

Oropharyngeal pain

Very common Diarrhoea (1) Diarrhoea (1)

Stomatitis Stomatitis

Abdominal pain

Abdominal pain upper

Common Rectal haemorrhage Abdominal pain

Fistula (1) Abdominal pain upper

Aphthous stomatitis

Haemorrhoids

Proctalgia

Toothache

Uncommon GI perforation (1) GI perforation (1)

Rectal haemorrhage

Fistula (1)

Aphthous stomatitis

Proctalgia

Very common Increased AST (2)

Increased ALT (2)

Common Increased AST (2)

Increased ALT (2)

Very common Palmar-Plantar Erythrodysaesthesiasyndrome

Common Skin hyperpigmentation Palmar-Plantar Erythrodysaesthesiasyndrome

Uncommon Compromised wound healing (1) Compromised wound healing (1)

System Organ Class Adverse Reaction

Frequency Category All grades Grades ≥3

Uncommon Osteonecrosis of the Jaw (ONJ)

Very common Proteinuria (1),(3)

Increased serum creatinine

Common Proteinuria (1),(3)

Uncommon Nephrotic syndrome (1) Nephrotic syndrome (1)

Thrombotic microangiopathy (1) Thrombotic microangiopathy (1)

Very common Asthenic conditions Asthenic conditions

Note: Adverse reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTCversion 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 withaflibercept as monotherapy and in combination with chemotherapies other than FOLFIRI

In the pivotal MCRC study, anaemia, nausea, vomiting, constipation, alopecia, increased alkalinephosphatase, and hyperbilirubinaemia occurred in ≥ 20 % of patients. These were comparablebetween groups, and the difference between groups did not exceed ≥ 2 % incidence for the

ZALTRAP/FOLFIRI regimen.

Patients treated with ZALTRAP have an increased risk of haemorrhage, including severe andsometimes fatal haemorrhagic events. In the pivotal study of MCRC patients, episodes ofbleeding/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/FOLFIRIregimen. The most common reported form of bleeding was minor (grade 1-2) epistaxis occurring in27.7 % 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 patientsreceiving the ZALTRAP/FOLFIRI regimen compared with 1.7 % of patients receiving theplacebo/FOLFIRI regimen. In other studies, severe intracranial haemorrhage and pulmonaryhaemorrhage/haemoptysis including fatal events have occurred in patients receiving ZALTRAP (seesection 4.4).

Gastrointestinal perforation

GI perforation including fatal GI perforation has been reported in patients treated with ZALTRAP. Inthe 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 theplacebo/FOLFIRI regimen. Grade 3-4 GI perforation events occurred in all 3 patients (0.5 %) treatedwith the ZALTRAP/FOLFIRI regimen and in 2 patients (0.3 %) treated with the placebo/FOLFIRIregimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lungcancer 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 in0.8 % 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. Inthe 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/FOLFIRIregimen 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 1placebo-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 % forpatients treated with ZALTRAP and 0.2 % for patients treated with placebo. Grade 3-4 fistulaoccurred in 0.2 % of patients treated with ZALTRAP and 0.1 % of patients treated with placebo (seesection 4.4).

In the pivotal study of MCRC patients, hypertension (all grades) has been reported in 41.2 % ofpatients treated with ZALTRAP/FOLFIRI and 10.7 % of patients treated with placebo/FOLFIRI. Anincreased risk of grade 3-4 hypertension (including hypertension and one case of essentialhypertension) has been observed in patients receiving the ZALTRAP/FOLFIRI regimen.

Grade 3 hypertension (requiring adjustment in existing anti-hypertensive therapy or treatment withmore than one medicinal product) was reported in 1.5 % of patients treated with the placebo/FOLFIRIregimen 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 developinggrade 3-4 hypertension, 54 % had onset during the first two cycles of treatment (see section 4.4).

Thrombotic and embolic events

In the pivotal study of MCRC patients, ATE (including transient ischaemic attack, cerebrovascularaccident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, andischaemic colitis) were reported in 2.6 % of patients treated with the ZALTRAP/FOLFIRI regimenand 1.5 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 events occurred in11 patients (1.8 %) treated with the ZALTRAP/FOLFIRI regimen and 3 patients (0.5 %) treated withthe 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 % forpatients treated with ZALTRAP and 1.7 % for patients treated with placebo. Grade 3-4 ATE occurredin 1.7 % of patients treated with ZALTRAP and 1.0 % of patients treated with placebo (see section4.4).

VTE include deep venous thrombosis and pulmonary embolism. In the pivotal study of MCRCpatients, all grades VTE occurred in 9.3 % of patients treated with the ZALTRAP/FOLFIRI regimenand 7.3 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 VTE occurred in 7.9 % ofpatients treated with the ZALTRAP/FOLFIRI regimen and in 6.3 % of patients treated with theplacebo/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 cancerpopulations), the incidence of VTE (all grades) was 7.1 % for patients treated with ZALTRAP and7.1 % for patients treated with placebo.

Proteinuria

In the pivotal study of MCRC patients, proteinuria (compiled from clinical and laboratory data) wasreported 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 % ofpatients treated with the ZALTRAP/FOLFIRI regimen compared to 1.2 % of patients treated with theplacebo/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/FOLFIRIregimen. One patient treated with the ZALTRAP/FOLFIRI regimen presenting with proteinuria andhypertension was diagnosed with thrombotic microangiopathy (TMA). Across the three Phase IIIplacebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidenceof nephrotic syndrome was 0.5 % of patients treated with ZALTRAP and 0.1 % of patients treatedwith 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 patientstreated 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/FOLFIRIregimen compared to 29.5 % patients treated with the placebo/FOLFIRI regimen. The most commongrade 3-4 neutropenic complication was the occurrence of febrile neutropenia in 4.3 % of patientstreated with the ZALTRAP/FOLFIRI regimen compared to 1.7 % of patients treated with theplacebo/FOLFIRI regimen. Grade 3-4 neutropenic infection/sepsis occurred in 1.5 % of patientstreated with the ZALTRAP/FOLFIRI regimen and 1.2 % of patients treated with the placebo/FOLFIRIregimen (see section 4.4).

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, upperrespiratory 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 patientstreated 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 % ofpatients treated with placebo/FOLFIRI. Grade 3-4 diarrhoea was reported in 19.3 % of patients treatedwith the ZALTRAP/FOLFIRI regimen compared to 7.8 % of patients treated with theplacebo/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/FOLFIRIregimen (see section 4.4).

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 theplacebo/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 woundhealing was reported in 3 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and5 patients (0.8 %) treated with the placebo/FOLFIRI regimen. Grade 3 compromised wound healingwas reported in 2 patients (0.3 %) treated with the ZALTRAP/FOLFIRI regimen and in none of thepatients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlledclinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of compromisedwound healing (all grades) was 0.5 % for patients treated with ZALTRAP and 0.4 % for patientstreated with placebo. Grade 3-4 compromised wound healing occurred in 0.2 % of patients treatedwith 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 wasreported in patients treated with monotherapy ZALTRAP (0.5 %) and in combination with otherchemotherapies (see section 4.4).

Additional adverse reactions and laboratory abnormalities reported with a ≥5 % difference (allgrades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRIregimen

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/FOLFIRIregimen (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 % versus1.7% 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 % allgrades; 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 % allgrades; 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 % versus2.8 % all grades; 0 versus 0 Grades 3-4).

The safety in paediatric patients has not been established.

Of the 611 patients treated with the ZALTRAP/FOLFIRI regimen in the pivotal study of MCRCpatients, 172 (28.2 %) were aged ≥ 65 and < 75 and 33 (5.4 %) were age ≥ 75. Elderly (≥ 65 yearsof 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 youngerpatients. Elderly people should be closely monitored for the development of diarrhoea and potentialdehydration (see section 4.4).

In patients receiving ZALTRAP, the adverse reactions in patients with mild renal impairment atbaseline in three Phase III placebo-controlled clinical studies (N = 352) were comparable with those ofpatients without renal impairment (N = 642). A limited number of patients having moderate/severerenal impairment at baseline (N = 49) were treated with ZALTRAP. In these patients, non-renal eventswere generally comparable between patients with renal impairment and those without renalimpairment, except a > 10 % higher incidence in dehydration (all grades) was noted (see section 4.4).

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 notdetected 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 pivotalstudy of MCRC patients, positive responses in the ADA assay were observed at higher levels inpatients 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 inthe 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 noobserved impact on the pharmacokinetic profile of aflibercept in patients who were positive in theimmunogenicity assays.

Given the similar ADA assay results in patients treated with placebo or ZALTRAP, the actualincidence 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, andunderlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP withthe incidence of antibodies to other products may be misleading.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX44

Vascular endothelial growth factor A and B (VEGF-A, VEGF-B), and placental growth factor (PlGF)are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic,and vascular permeability factors for endothelial cells. VEGF-A acts via two receptor tyrosine kinases,

VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF and VEGF-B bind only to

VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptorsby VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF isalso linked to pathological neovascularisation and recruitment of inflammatory cells into tumours.

Aflibercept, also known as VEGF TRAP in the scientific literature, is a recombinant fusion proteinconsisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technologyin a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimericglycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation,constituting an additional 15 % of the total molecular mass, resulting in a total molecular weight of115 kDa.

Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its nativereceptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, afliberceptprevents binding of endogenous ligands to their cognate receptors and thereby blocks receptormediated signaling.

Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, therebyinhibiting the growth of new vessels that supply tumours with oxygen and nutrients.

Aflibercept binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for

VEGF-A165 and 0.36 pM for VEGF-A121), to human PlGF (KD of 39 pM for PlGF-2), and to human

VEGF-B (KD of 1.92 pM) to form a stable, inert complex which has no detectable biological activity.

Administration of aflibercept to mice bearing xenotransplant or allotransplant tumours inhibited thegrowth of various cancer types.

The efficacy and safety of ZALTRAP were evaluated in a randomised, double-blind,placebo-controlled study in patients with metastatic colorectal cancer who had previously been treatedwith an oxaliplatin-based treatment with or without prior bevacizumab. A total of 1,226 patients wererandomised (1:1) to receive either ZALTRAP (N = 612; 4 mg/kg as a 1 hour intravenous infusion onday 1) or placebo (N = 614), in combination with 5-fluouracil plus irinotecan [FOLFIRI: irinotecan180 mg/m2 intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² intravenousinfusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-FU 400 mg/m²intravenous bolus, followed by 5-FU 2,400 mg /m² continuous intravenous infusion over 46-hours].

The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until diseaseprogression or unacceptable toxicity. The primary efficacy endpoint was overall survival. Treatmentassignment was stratified by the ECOG performance status (0 versus 1 versus 2) and according toprior therapy with bevacizumab (yes or no).

Demographics were well balanced between the treatment arms (age, race, ECOG performance status,and prior bevacizumab status). Of the 1,226 patients randomised in the study, the median age was61 years, 58.6 % were male, 97.8 % had a baseline ECOG performance status (PS) of 0 or 1, and2.2 % had a baseline ECOG performance status (PS) of 2. Among the 1,226 randomised patients,89.4 % and 90.2 % of patients treated with the placebo/FOLFIRI and ZALTRAP/FOLFIRI regimens,respectively, received prior oxaliplatin-based combination chemotherapy in the metastatic/advancedsetting. Approximately 10 % of patients (10.4 % and 9.8 % of patients treated with theplacebo/FOLFIRI and ZALTRAP/FOLFIRI regimens, respectively) received prior oxaliplatin-basedadjuvant chemotherapy and progressed on or within 6 months of completion of adjuvantchemotherapy. Oxaliplatin-based regimens were administered in combination with bevacizumab in373 patients (30.4 %).

Overall efficacy results for the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimenare summarised in Figure 1 and Table 2.

Figure 1 - Overall survival (months) - Kaplan-Meier curves by treatment group - ITT population

Table 2 - Main efficacy endpointsa - ITT population

Placebo/FOLFIRI ZALTRAP/FOLFIRI(N = 614) (N = 612)

OS

Number of death events, n (%) 460 (74.9 %) 403 (65.8 %)

Median overall survival (95 % CI) (months) 12.06 (11.07 to 13.08) 13.50 (12.52 to 14.95)

Stratified hazard ratio (95 % CI) 0.817 (0.714 to 0.935)

Stratified log-rank test p-value 0.0032

PFSb

Number of events, n (%) 454 (73.9 %) 393 (64.2 %)

Median PFS (95 % CI) (months) 4.67 (4.21 to 5.36) 6.90 (6.51 to 7.20)

Stratified hazard ratio (95 % CI) 0.758 (0.661 to 0.869)

Stratified log-rank test p-value 0.00007

Overall Response Rate (CR+PR) (95 % CI) (%)c 11.1 (8.5 to 13.8) 19.8 (16.4 to 23.2)

Stratified Cochran-Mantel-Haenszel testp-value 0.0001a Stratified on ECOG performance status (0 versus 1 versus 2) and prior bevacizumab (yes versus no).b PFS (based on tumour assessment by the IRC): Significance threshold is set to 0.0001c Overall objective response rate by IRC

OS and PFS by stratification factors were performed. A numerically lower treatment effect on OS withthe ZALTRAP/FOLFIRI regimen was reported for patients with prior bevacizumab as compared topatients without prior bevacizumab exposure, with no evidence of heterogeneity in treatment effect(non significant interaction test). Results by prior bevacizumab exposure are summarised in Table 3.

Table 3 - OS and PFS by prior bevacizumab exposurea - ITT population

Placebo/FOLFIRI ZALTRAP/FOLFIRI(N = 614) (N = 612)

OS

Patients with prior bevacizumab (n (%)) 187 (30.5 %) 186 (30.4 %)

Median OS (95 % CI) (months) 11.7 (9.96 to 13.77) 12.5 (10.78 to 15.47)

Hazard ratio (95 % CI) 0.862 (0.676 to 1.100)

Patients with no prior bevacizumab (n (%)) 427 (69.5 %) 426 (69.6 %)

Median OS (95 % CI) (months) 12.4 (11.17 to 13.54) 13.9 (12.72 to 15.64)

Hazard ratio (95 % CI) 0.788 (0.671 to 0.925)

PFS

Patients with prior bevacizumab (n (%)) 187 (30.5 %) 186 (30.4 %)

Median PFS (95 % CI) (months) 3.9 (3.02 to 4.30) 6.7 (5.75 to 8.21)

Hazard ratio (95 % CI) 0.661 (0.512 to 0.852)

Patients with no prior bevacizumab (n (%)) 427 (69.5 %) 426 (69.6 %)

Median PFS (95 % CI) (months) 5.4 (4.53 to 5.68) 6.9 (6.37 to 7.20)

Hazard ratio (95 % CI) 0.797 (0.679 to 0.936)a As determined per IVRS

Analysis for OS and PFS by ECOG PS was also performed. The hazard ratio (95 % CI) of overallsurvival was 0.77 (0.64 to 0.93) for ECOG performance status 0 and 0.87 (0.71 to 1.06) for ECOGperformance status 1. The hazard ratio (95 % CI) of progression free survival was 0.76 (0.63 to 0.91)for ECOG performance status 0 and 0.75 (0.61 to 0.92) for ECOG performance status 1.

Post-hoc analyses excluding patients who progressed during or within 6 months of adjuvant therapyfor patients with or without prior bevacizumab treatment are summarised in Table 4.

Table 4 - Post-hoc analyses excluding adjuvant patientsa,b

Placebo/FOLFIRI ZALTRAP/FOLFIRI(N=550) (N=552)

Patients with prior bevacizumab excluding adjuvant 179 (32.5 %) 177 (32.1 %)only (n (%))

Median OS (95 % CI) (months) 11.7 (9.66 to 13.27) 13.8 (11.01 to 15.87)

Hazard ratio (95 % CI) 0.812 (0.634 to 1.042)

Median PFS (95 % CI) (months) 3.9 (3.02 to 4.30) 6.7 (5.72 to 8.21)

Hazard ratio (95 % CI) 0.645 (0.498 to 0.835)

Patients with no prior bevacizumab excluding adjuvant 371 (67.5 %) 375 (67.9 %)only (n ( %))

Median overall survival (95 % CI) (months) 12.4 (11.17 to 13.54) 13.7 (12.71 to 16.03)

Hazard ratio (95 % CI) 0.766 (0.645 to 0.908)

Median PFS (95 % CI) (months) 5.3 (4.50 to 5.55) 6.9 (6.24 to 7.20)

Hazard ratio (95 % CI) 0.777 (0.655 to 0.921)a As determined per IVRSb OS in ITT population excluding patients who progressed during or within 6 months of adjuvant therapydemonstrated an HR (95 % CI) of 0.78 (0.68 to 0.90) [median OS (95 % CI) with Placebo/FOLFIRI11.9 months (10.88 to 13.01) and with ZALTRAP/FOLFIRI 13.8 months (12.68 to 15.44)]

Other subgroup analyses for overall survival and progression free survival according toage (< 65; ≥ 65), gender, presence of liver metastasis only, history of prior hypertension, and numberof organs involved, showed a treatment effect favouring the ZALTRAP/FOLFIRI regimen over theplacebo/FOLFIRI regimen.

In sub-group analysis of overall survival, a benefit consistent with the overall population was observedin patients < 65 years old and ≥ 65 years old who received the ZALTRAP/FOLFIRI regimen.

Exploratory biomarker analyses were undertaken in the VELOUR trial including analyses of

RAS mutational status in 482 of 1,226 patients (n = 240 aflibercept; 242 placebo). In patients with

RAS wild type tumours the HR (95 % CI) for OS was 0.7 (0.5-1.0) with a median OS of 16.0 monthsfor patients treated with aflibercept, and 11.7 months for the patients treated with placebo.

Corresponding data in patients with RAS mutant type tumours showed a HR for OS of 0.9 (0.7-1.2)with median 12.6 and 11.2 months for aflibercept and placebo, respectively. These data areexploratory and the statistical interaction test was non-significant (lack of evidence for heterogeneityin treatment effect between the RAS wild-type and RAS mutant subgroups).

The European Medicines Agency has waived the obligation to conduct studies with ZALTRAP in allsubsets of the paediatric population in adenocarcinoma of the colon and rectum (see section 4.2 forinformation on paediatric use).

The pharmacokinetic properties described below have to a large extent been derived from a populationpharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies.

In preclinical tumour models, biologically active doses of aflibercept correlated with those necessaryto produce circulating concentrations of free aflibercept in excess of VEGF-bound aflibercept.

Circulating concentrations of VEGF-bound aflibercept increase with the aflibercept dose until mostavailable VEGF is bound. Further increases in the aflibercept dose resulted in dose-related increases incirculating free aflibercept concentrations but only small further increases in the VEGF-boundaflibercept concentration.

In patients, ZALTRAP is administered at the dose of 4 mg/kg intravenously every two weeks forwhich there is an excess of circulating free aflibercept compared to VEGF-bound aflibercept.

At the recommended dose regimen of 4 mg/kg every two weeks, concentration of free afliberceptwere near steady-state levels by the second cycle of treatment with essentially no accumulation(accumulation ratio of 1.2 at steady-state compared to the first administration).

The volume of distribution of free aflibercept at steady-state is approximately 8 litres.

No metabolism studies have been conducted with aflibercept since it is a protein. Aflibercept isexpected to degrade to small peptides and individual amino acids.

Free aflibercept is primarily cleared by binding to endogenous VEGF to form a stable, inactivecomplex. As with other large proteins, both free and bound aflibercept, are expected to be cleared,more slowly, by other biological mechanisms, such as proteolytic catabolism.

At doses greater than 2 mg/kg, free aflibercept clearance was approximately 1.0L/day with a terminalhalf-life of 6 days.

High molecular weight proteins are not cleared by the renal route, therefore renal elimination ofaflibercept is expected to be minimal.

Consistent with target-mediated drug disposition, free aflibercept exhibits a faster (non-linear)clearance at doses below 2 mg/kg, likely due to the high affinity binding of aflibercept to endogenous

VEGF. Linear clearance observed in the dose range of 2 to 9 mg/kg is likely due to non saturablebiological mechanisms of elimination such as protein catabolism.

There was no effect of age on the pharmacokinetics of free aflibercept.

No effect of race was identified in the population analysis.

Gender was the most significant covariate for explaining the interindividual variability of freeaflibercept clearance and volume with a 15.5 % higher clearance and a 20.6 % higher volume ofdistribution in males than in females. These differences do not affect exposure due to weight-baseddosing and no dose modifications based on gender are required.

Weight

Weight had an effect on free aflibercept clearance and volume of distribution resulting with a 29 %increase in aflibercept exposure in patients weighing ≥ 100 kg.

There have been no formal studies with ZALTRAP in patients with hepatic impairment. In apopulation pharmacokinetic analysis with data from 1,507 patients with various types of advancedmalignancies receiving ZALTRAP with or without chemotherapy, 63 patients with mild hepaticimpairment (total bilirubin > 1.0 x - 1.5 x ULN and any AST) and 5 patients with moderate hepaticimpairment (total bilirubin > 1.5 x - 3 x ULN and any AST) were treated with ZALTRAP. In thesemild and moderate hepatic impairment patients, there was no effect on clearance of aflibercept. Thereare no data available for patients with severe hepatic impairment (total bilirubin > 3 x ULN and any

AST).

There have been no formal studies with ZALTRAP in patients with renal impairment. A populationpharmacokinetic analysis was conducted with data from 1,507 patients with various types of advancedmalignancies receiving ZALTRAP with or without chemotherapy. This population included;549 patients with mild renal impairment (CL CR between 50-80 ml/min), 96 patients with moderaterenal impairment (CL CR between 30-50 ml/min), and 5 patients with severe renal impairment(CL CR < 30 ml/min). This population pharmacokinetic analysis revealed no clinically meaningfuldifferences in clearance or systemic exposure (AUC) of free aflibercept in patients with moderate andmild renal impairment at the 4 mg/kg dose of ZALTRAP as compared to the overall populationstudied. No conclusion can be drawn for patients with severe renal impairment due to very limiteddata available. In the few patients with severe renal impairment, drug exposure was similar to thatobserved in patients with normal renal function.

Weekly/every two weeks intravenous administration of aflibercept to cynomolgus monkeys for up to6 months resulted in changes in the bone (effects on growth plate and the axial andappendicular skeleton), nasal cavity, kidney, ovary, and adrenal gland. Most aflibercept-relatedfindings were noted from the lowest dose tested corresponding to plasma exposures close to those inpatients at the therapeutic dose. Most aflibercept-induced effects were reversible after a 5-month drugfree period with the exception of skeletal and nasal cavity findings. Most findings were considered tobe related to the pharmacological activity of aflibercept.

Aflibercept administration resulted in a delay in wound healing in rabbits. In full-thickness excisionaland incisional skin wound models, aflibercept administration reduced fibrous response,neovascularisation, epidermal hyperplasia/re-epithelialisation, and tensile strength. Afliberceptincreased blood pressure in normotensive rodents.

Carcinogenesis and mutagenesis

No studies have been conducted to evaluate carcinogenicity or mutagenicity of aflibercept.

No specific studies with aflibercept have been conducted in animals to evaluate the effect on fertility.

However, results from a repeat dose toxicity study suggest there is a potential for aflibercept to impairreproductive function and fertility. In sexually mature female cynomolgus monkeys inhibition ofovarian function and follicular development was evidenced. These animals also lost normal menstrualcycling. In sexually mature male cynomolgus monkeys a decrease in sperm motility and an increase inincidence of morphological abnormalities of spermatozoa were observed. There was no margin ofexposure to patients in relation to these effects. These effects were fully reversible within 8-18 weeksafter the last injection.

Reproductive and developmental toxicology

Aflibercept has been shown to be embryotoxic and teratogenic when administered intravenously topregnant rabbits every 3 days during the organogenesis period (gestation days 6 to18) at dosesapproximately 1 to 15 times the human dose of 4 mg/kg every 2 weeks. Observed effects includeddecreases in maternal body weights, an increased number of foetal resorptions, and an increasedincidence of external, visceral, and skeletal foetal malformations.

Sucrose

Sodium chloride

Sodium citrate dihydrate

Citric acid monohydrate

Polysorbate 20

Sodium phosphate dibasic heptahydrate

Sodium phosphate monobasic monohydrate

Sodium hydroxide and/or hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts or solvents except those mentioned in section 6.6.

Unopened vial3 years

After dilution in the infusion bag

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C and for8 hours at 25°C.

From a microbiological point of view, the solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place incontrolled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C).

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

* 4 ml of concentrate in a 5 ml clear borosilicate glass vial (type I) sealed by a flanged stopperwith flip-off cap and inserted coated sealing disc. Pack size of 1 vial or 3 vials.

* 8 ml of concentrate in a 10 ml clear borosilicate glass vial (type I) sealed by a flanged stopperwith flip-off cap and inserted coated sealing disc. Pack size of 1 vial.

Not all pack sizes may be marketed.

ZALTRAP is a sterile, preservative-free and non-pyrogenic concentrate, therefore the solution forinfusion should be prepared by a healthcare professional using safe-handling procedures and aseptictechnique.

Caution should be exercised when handling ZALTRAP, taking into account the use of containmentdevices, personal protective equipment (e.g. gloves), and preparation procedures.

Preparation of the infusion solution

* Inspect the ZALTRAP vial visually prior to use. The concentrate solution must be clear andwithout particles.

* Based on the required dose for the patient, withdraw the necessary volume of ZALTRAPconcentrate from the vial. More than one vial could be needed for the preparation of theinfusion solution.

* Dilute it to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution or5 % glucose solution for infusion. The concentration of the final ZALTRAP solution forintravenous infusion should be kept within the range of 0.6 mg/ml to 8 mg/ml of aflibercept.

* PVC containing DEHP infusion bags or polyolefin infusion bags should be used.

* The diluted solution should be inspected visually for particulate matter and discolourationprior to administration. If any discolouration or particulate matter is observed, thereconstituted solution should be discarded.

* ZALTRAP is a single-use vial. Do not re-enter the vial after the initial puncture. Any unusedconcentrate should be discarded.

Administration of the infusion solution

Diluted solutions of ZALTRAP should be administered using infusion sets containing a 0.2 micronpolyethersulfone filter.

The infusion sets should be made of one of the following materials:

* polyvinyl chloride (PVC) containing bis(2-ethylhexyl) phthalate (DEHP)

* DEHP free PVC containing trioctyl-trimellitate (TOTM)

* polypropylene

* polyethylene lined PVC

* polyurethane

Filters made of polyvinylidene fluoride (PVDF) or nylon must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/12/814/001

EU/1/12/814/002

EU/1/12/814/003

AUTHORISATION

Date of first authorisation: 01 February 2013

Date of latest renewal: 21 September 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu