Zaltrap

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

ZALTRAP 25 mg/ml concentrate for solution for infusion  

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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 by 

recombinant DNA technology. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Concentrate for solution for infusion (sterile concentrate). 

The concentrate is a clear colourless to pale yellow solution. 

 

 

4. CLINICAL PARTICULARS 

 

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.  



 

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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 



 

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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).  

 



 

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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 



 

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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 



 

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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). 



 

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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).  

 

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 males and 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 and 

fertile males should use effective contraception during and up to a minimum of 6 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 



 

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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). 

 

 

 



 

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

the MCRC study 

 

System Organ Class Adverse Reaction 

Frequency Category 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  



 

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System Organ Class Adverse Reaction 

Frequency Category All grades Grades ≥3 

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 



 

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System Organ Class Adverse Reaction 

Frequency Category All grades Grades ≥3 

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 



 

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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).  



 

14 

 

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 % 



 

15 

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. 



 

16 

 

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 the national reporting system 

listed in Appendix V. 

 

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). 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

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

 

Mechanism of action 

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 receptors 

by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF is 

also 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 protein 

consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 

2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technology 

in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimeric 

glycoprotein 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 of 

115 kDa. 

 

Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native 

receptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, aflibercept 

prevents binding of endogenous ligands to their cognate receptors and thereby blocks receptor 

mediated signaling.   

 

Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby 

inhibiting 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. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

17 

Pharmacodynamic effects   

Administration of aflibercept to mice bearing xenotransplant or allotransplant tumours inhibited the 

growth of various cancer types. 

 

 

 

Clinical efficacy and safety  

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 treated 

with an oxaliplatin-based treatment with or without prior bevacizumab. A total of 1,226 patients were 

randomised (1:1) to receive either ZALTRAP (N = 612; 4 mg/kg as a 1 hour intravenous infusion on 

day 1) or placebo (N = 614), in combination with 5-fluouracil plus irinotecan [FOLFIRI: 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-FU 400 mg/m² 

intravenous 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 disease 

progression or unacceptable toxicity. The primary efficacy endpoint was overall survival. Treatment 

assignment was stratified by the ECOG performance status (0 versus 1 versus 2) and according to 

prior 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 was 

61 years, 58.6 % were male, 97.8 % had a baseline ECOG performance status (PS) of 0 or 1, and 

2.2 % 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/advanced 

setting. Approximately 10 % of patients (10.4 % and 9.8 % of patients treated with the 

placebo/FOLFIRI and ZALTRAP/FOLFIRI regimens, respectively) received prior oxaliplatin-based 

adjuvant chemotherapy and progressed on or within 6 months of completion of adjuvant 

chemotherapy. Oxaliplatin-based regimens were administered in combination with bevacizumab in 

373 patients (30.4 %). 

 

Overall efficacy results for the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen 

are summarised in Figure 1 and Table 2. 



 

18 

 

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

 

 



 

19 

 

Table 2 - Main efficacy endpointsa – ITT population 

 

 

Placebo/FOLFIRI 

(N = 614) 

ZALTRAP/FOLFIRI 

(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 test 

p-value 0.0001 
a 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 0.0001 
c Overall objective response rate by IRC  

 

OS and PFS by stratification factors were performed. A numerically lower treatment effect on OS with 

the ZALTRAP/FOLFIRI regimen was reported for patients with prior bevacizumab as compared to 

patients 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 

(N = 614) 

ZALTRAP/FOLFIRI 

(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 overall 

survival was 0.77 (0.64 to 0.93) for ECOG performance status 0 and 0.87 (0.71 to 1.06) for ECOG 



 

20 

performance 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 therapy 

for patients with or without prior bevacizumab treatment are summarised in Table 4. 

 

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

 

 Placebo/FOLFIRI 

(N=550) 

ZALTRAP/FOLFIRI 

(N=552) 

Patients with prior bevacizumab excluding adjuvant 

only (n (%)) 

179 (32.5 %) 177 (32.1 %) 

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 only (n ( %)) 
371 (67.5 %) 375 (67.9 %) 

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 IVRS 
b OS in ITT population excluding patients who progressed during or within 6 months of adjuvant therapy 

demonstrated an HR (95 %  CI) of 0.78 (0.68 to 0.90) [median OS (95 %  CI) with Placebo/FOLFIRI 

11.9 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 to 

age (< 65; ≥ 65), gender, presence of liver metastasis only, history of prior hypertension, and number 

of organs involved, showed a treatment effect favouring the ZALTRAP/FOLFIRI regimen over the 

placebo/FOLFIRI regimen.  

 

In sub-group analysis of overall survival, a benefit consistent with the overall population was observed 

in 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 months 

for 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 are 

exploratory and the statistical interaction test was non-significant (lack of evidence for heterogeneity 

in treatment effect between the RAS wild-type and RAS mutant subgroups). 

 

Paediatric population 

The European Medicines Agency has waived the obligation to conduct studies with ZALTRAP in all 

subsets of the paediatric population in adenocarcinoma of the colon and rectum (see section 4.2 for 

information on paediatric use).  

 

5.2 Pharmacokinetic properties  

 

The pharmacokinetic properties described below have to a large extent been derived from a population 

pharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies.  

 

 



 

21 

Absorption 

In preclinical tumour models, biologically active doses of aflibercept correlated with those necessary 

to produce circulating concentrations of free aflibercept in excess of VEGF-bound aflibercept. 

Circulating concentrations of VEGF-bound aflibercept increase with the aflibercept dose until most 

available VEGF is bound. Further increases in the aflibercept dose resulted in dose-related increases in 

circulating free aflibercept concentrations but only small further increases in the VEGF-bound 

aflibercept concentration.   

 

In patients, ZALTRAP is administered at the dose of 4 mg/kg intravenously every two weeks for 

which 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 aflibercept 

were 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). 

 

Distribution 

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

 

Biotransformation 

No metabolism studies have been conducted with aflibercept since it is a protein. Aflibercept is 

expected to degrade to small peptides and individual amino acids.  

 

Elimination 

Free aflibercept is primarily cleared by binding to endogenous VEGF to form a stable, inactive 

complex. 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 terminal 

half-life of 6 days.  

 

High molecular weight proteins are not cleared by the renal route, therefore renal elimination of 

aflibercept is expected to be minimal.   

 

Linearity/non-linearity 

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 saturable 

biological mechanisms of elimination such as protein catabolism. 

 

Other special populations 

Elderly 

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

 

Race 

No effect of race was identified in the population analysis. 

 

Gender 

Gender was the most significant covariate for explaining the interindividual variability of free 

aflibercept clearance and volume with a 15.5 % higher clearance and a 20.6 % higher volume of 

distribution in males than in females. These differences do not affect exposure due to weight-based 

dosing 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.  

 

 



 

22 

Hepatic impairment 

There have been no formal studies with ZALTRAP in patients with hepatic impairment. In a 

population pharmacokinetic analysis with data from 1,507 patients with various types of advanced 

malignancies receiving ZALTRAP with or without chemotherapy, 63 patients with mild hepatic 

impairment (total bilirubin > 1.0 x – 1.5 x ULN and any AST) and 5 patients with moderate hepatic 

impairment (total bilirubin > 1.5 x – 3 x ULN and any AST) were treated with ZALTRAP. In these 

mild and moderate hepatic impairment patients, there was no effect on clearance of aflibercept. There 

are no data available for patients with severe hepatic impairment (total bilirubin > 3 x ULN and any 

AST). 

 

Renal impairment  

There have been no formal studies with ZALTRAP in patients with renal impairment. A population 

pharmacokinetic analysis was conducted with data from 1,507 patients with various types of advanced 

malignancies 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 moderate 

renal 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 meaningful 

differences in clearance or systemic exposure (AUC) of free aflibercept in patients with moderate and 

mild renal impairment at the 4 mg/kg dose of ZALTRAP as compared to the overall population 

studied. No conclusion can be drawn for patients with severe renal impairment due to very limited 

data available. In the few patients with severe renal impairment, drug exposure was similar to that 

observed in patients with normal renal function. 

 

5.3 Preclinical safety data 

 

Animal toxicology and pharmacology 

Weekly/every two weeks intravenous administration of aflibercept to cynomolgus monkeys for up to 

6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular 

 skeleton), nasal cavity, kidney, ovary, and adrenal gland. Most aflibercept-related findings were noted 

from the lowest dose tested corresponding to plasma exposures close to those in patients at the 

therapeutic dose. Most aflibercept-induced effects were reversible after a 5-month drug free period 

with the exception of skeletal and nasal cavity findings. Most findings were considered to be related to 

the pharmacological activity of aflibercept.  

 

Aflibercept administration resulted in a delay in wound healing in rabbits. In full-thickness excisional 

and incisional skin wound models, aflibercept administration reduced fibrous response, 

neovascularisation, epidermal hyperplasia/re-epithelialisation, and tensile strength. Aflibercept 

increased blood pressure in normotensive rodents. 

 

Carcinogenesis and mutagenesis 

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

 

Impairment of fertility 

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 impair 

reproductive function and fertility. In sexually mature female cynomolgus monkeys inhibition of 

ovarian function and follicular development was evidenced. These animals also lost normal menstrual 

cycling. In sexually mature male cynomolgus monkeys a decrease in sperm motility and an increase in 

incidence of morphological abnormalities of spermatozoa were observed. There was no margin of 

exposure to patients in relation to these effects. These effects were fully reversible within 8-18 weeks 

after the last injection.  

 

Reproductive and developmental toxicology 

Aflibercept has been shown to be embryotoxic and teratogenic when administered intravenously to 

pregnant rabbits every 3 days during the organogenesis period (gestation days 6 to18) at doses 

approximately 1 to 15 times the human dose of 4 mg/kg every 2 weeks. Observed effects included 



 

23 

decreases in maternal body weights, an increased number of foetal resorptions, and an increased 

incidence of external, visceral, and skeletal foetal malformations. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

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  

 

6.2 Incompatibilities 

 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 

products or solvents except those mentioned in section 6.6.  

 

6.3 Shelf life 

 

Unopened vial 

3 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 for 

8 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 the 

user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in 

controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

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.  

 

6.5 Nature and contents of container 
 

• 4 ml of concentrate in a 5 ml clear borosilicate glass vial (type I) sealed by a flanged stopper 
with 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 stopper 
with flip-off cap and inserted coated sealing disc. Pack size of 1 vial. 

 

Not all pack sizes may be marketed.  

 

6.6 Special precautions for disposal and other handling 



 

24 

 

ZALTRAP is a sterile, preservative-free and non-pyrogenic concentrate, therefore the solution for 

infusion should be prepared by a healthcare professional using safe-handling procedures and aseptic 

technique. 

 

Caution should be exercised when handling ZALTRAP, taking into account the use of containment 

devices, 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 and 

without particles.  

• Based on the required dose for the patient, withdraw the necessary volume of ZALTRAP 
concentrate from the vial. More than one vial could be needed for the preparation of the 

infusion solution.  

• Dilute it to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution or 
5 % glucose solution for infusion. The concentration of the final ZALTRAP solution for 

intravenous 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 discolouration 

prior to administration. If any discolouration or particulate matter is observed, the 

reconstituted solution should be discarded. 

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

 

Administration of the infusion solution 

Diluted solutions of ZALTRAP should be administered using infusion sets containing a 0.2 micron 

polyethersulfone 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.  

 

Disposal 

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

requirements. 

 

7. MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 

75008 Paris 

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/814/001 

EU/1/12/814/002 



 

25 

EU/1/12/814/003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 

 

Date of first authorisation: 01 February 2013 

Date of latest renewal: 21 September 2017 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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



 

26 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 

B.    CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  

AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 



 

27 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance  

Regeneron Pharmaceuticals, Inc. 

81 Columbia Turnpike 

Rensselaer, NY 12144 

USA 

 

Name and address of the manufacturer responsible for batch release 

Sanofi-aventis Deutschland GmbH 

Industriepark Höchst 

D-65926 Frankfurt am Main 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports  
The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal.  

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreeed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached.  

 

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 

same time. 

 

 



 

28 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  



 

30 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

ZALTRAP 25 mg / ml concentrate for solution for infusion 

aflibercept 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S ) 

 

One vial of 4 ml contains 100 mg of aflibercept (25 mg / ml). 

One vial of 8 ml contains 200 mg of aflibercept (25 mg / ml). 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains 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 and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

100 mg / 4 ml 

1 vial  

3 vials  

 

200 mg / 8 ml 

1 vial  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Single-dose vial. 

 

Read the package leaflet before use. 

 

For intravenous use only. Use only after dilution. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

 



 

31 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

Shelf life after dilution: see package leaflet.  

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 

75008 Paris 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/814/001 1 vial (100 mg/4 ml) 

EU/1/12/814/002 3 vials (100 mg/4 ml) 

EU/1/12/814/003 1 vial (200 mg/8 ml) 

 

 

13. BATCH NUMBER 

 

Batch 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted  

 

 

 

 

 



 

32 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

<2D barcode carrying the unique identifier included.> 

 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN: 

NN:  

 

 



 

33 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

ZALTRAP 25 mg / ml sterile concentrate 

aflibercept 

For intravenous use only. 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

100 mg / 4 ml 

200 mg / 8 ml 

 

 

6. OTHER 

 

 



 

34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

35 

Package leaflet: Information for the user 

 

ZALTRAP 25 mg / ml concentration for solution for infusion 

aflibercept 

 

 

Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 

• Keep this leaflet. You may need to read it again, or provide it to future healthcare providers. 

• If you have any further questions, ask your doctor, pharmacist or nurse. 

• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What ZALTRAP is and what it is used for 

2. What you need to know before you are given ZALTRAP 

3. How ZALTRAP is given 

4. Possible side effects 

5. How to store ZALTRAP 
6. Contents of the pack and other information 

 

 

1. What ZALTRAP is and what it is used for 
 

What ZALTRAP is and how it works 

ZALTRAP contains the active substance aflibercept, a protein that works by blocking the growth of 

new blood vessels within the tumour. The tumour needs nutrients and oxygen from blood in order to 

grow. By blocking the growth of blood vessels, ZALTRAP helps to stop or slow down the growth of 

the tumour. 

 

What ZALTRAP is used for 

ZALTRAP is a medicine used to treat advanced cancers of the colon or rectum (parts of the large 

intestine) in adults. It will be given with other medicines called ‘chemotherapy’, including 

‘5-fluorouracil’, ‘folinic acid’, and ‘irinotecan’.  

 

 

2. What you need to know before you are given ZALTRAP 
 

Do not use ZALTRAP: 

• if you are allergic to aflibercept or any of the other ingredients of this medicine (listed in section 
 6).  

• in your eye, since it may severely damage it. 
 

Please also read the package leaflets for the other medicines (‘chemotherapy’) that are part of your 

treatment, to see if they are suitable for you. If you are unsure, ask your doctor, pharmacist or nurse if 

there are any reasons why you cannot use these medicines. 

 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before you are given ZALTRAP and during your treatment if: 

• you have any bleeding problems or if you notice any bleeding after treatment (see section 4) or if 
you feel extreme tiredness, weakness, dizziness, or have changes in the colour of your stool. If the 

bleeding is severe, your doctor will stop your treatment with ZALTRAP. This is because 

ZALTRAP may increase the risk of bleeding. 

 



 

36 

• you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

planned tooth extraction and especially if you have previously been treated with a bisphosphonate 

(used to treat or prevent bone disorders). A side effect called osteonecrosis (bone damage in the 

jaw) has been reported in cancer patients treated with ZALTRAP. You may be advised to have a 

dental check-up before you start treatment with ZALTRAP. While being treated with ZALTRAP, 

you should maintain good oral hygiene (including regular teeth brushing) and receive routine 

dental check-ups. If you wear dentures you should make sure these fit properly. If you also have 

previously received or are receiving intravenous bisphosphonates dental treatment or dental 

surgery, (e.g. tooth extractions), should be avoided. Inform your doctor about your dental 

treatment and tell your dentist that you are being treated with ZALTRAP.  Contact your doctor 

and dentist immediately during and after treatment with ZALTRAP if you experience any 

problems with your mouth or teeth such as loose teeth, pain or swelling, or non-healing of sores or 

discharge, as these could be signs of osteonecrosis of the jaw. 

 

• you have illnesses where your gut is inflamed, such as an infected section of the bowel wall (also 
called ‘diverticulitis’), stomach ulcers or colitis. This is because ZALTRAP may increase the risk 

of developing holes in the gut wall. If this should happen to you, your doctor will stop your 

treatment with ZALTRAP. 

 

• you have had any abnormal tube-like connections or passageways inside the body between 
internal organs and skin or other tissues (also called ‘fistula’). If you develop such a connection or 

passageway during treatment, your doctor will stop your treatment with ZALTRAP. 

 

• you have high blood pressure. Zaltrap may increase blood pressure (see section 4) and your doctor 
will need to monitor your blood pressure and may adjust your blood pressure medicines or your 

dose of ZALTRAP. It is therefore also important to tell your doctor, pharmacist or nurse if you 

have other heart problems since high blood pressure could make these worse.  

 

• you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in 
a blood vessel wall. 

 

• you experience shortness of breath (dyspnea) when you exert yourself or when you lie down, 
excessive tiredness or leg swelling which may be signs of heart failure. 

 

• you experience signs of a blood clot (see section 4). The signs of a blood clot may vary depending 
on where it appears (e.g. lungs, leg, heart or brain) but may include symptoms such as chest pain, 

coughing, being short of breath or having difficulty breathing. Other signs may include swelling in 

one or both legs, pain or tenderness in one or both legs, discolouration and warmth of the skin on 

the affected leg or visible veins. It may also present itself as a sudden numb or weak feeling in the 

face, arms, or legs. Other signs include feeling confused, problems with sight, walking, 

coordination or balance, problems in saying words or slurring of speech. If you experience any of 

these symptoms, talk to your doctor immediatley since your doctor may want to treat your 

symptoms and stop your treatment with ZALTRAP. 

 

• you have kidney problems (protein in the urine), since your doctor will monitor your kidney 
function and may need to adjust your dose of ZALTRAP. 

 

• your number of white blood cells is too low. Zaltrap may reduce the number of white cells in your 
blood and your doctor will monitor your white blood cell count and may give you additional 

medicines to increase it. If your white blood cells are low, your doctor may need to delay your 

treatment. 

 

• you have severe or long-lasting diarrhoea, feel sick (nausea) or are being sick (vomiting) - these 
could cause severe loss of body fluids (called ‘dehydration’). Your doctor may need to treat you 

with other medicines and/or fluids given intravenously. 

 



 

37 

• you have ever had any allergies - serious allergic reactions can happen during treatment with 
ZALTRAP (see section 4). Your doctor may need to treat the allergic reaction or stop your 

treatment with ZALTRAP. 

 

• you have had a tooth removed or any form of surgery in the last 4 weeks, or you are going to have 
an operation or a dental or medical procedure, or you have a wound after surgery that has not 

healed. Your doctor will temporarily stop the treatment before and after surgery. 

 

• you experience fits (seizures). If you experience changes in your vision or confusion, your doctor 
may stop your treatment with ZALTRAP. 

 

• you are 65 years of age or older and experience diarrhoea, dizziness, weakness, weight loss, or 
severe loss of body fluids (called ‘dehydration’). Your doctor should monitor you carefully. 

 

• your level of everyday activities is limited or worsens on treatment. Your doctor should monitor 
you carefully. 

 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 

you are given ZALTRAP and during your treatment.  

 

During treatment, your doctor will perform a number of tests to monitor the function of your body and 

how the medicine is working. Tests may include blood and urine tests, x-ray or other scanning 

techniques and/or other tests. 

 

ZALTRAP is given by a drip (infusion) into one of your veins (‘intra-venous’) to treat advanced 

cancers of the colon or rectum. ZALTRAP must not be injected into the eye, since it may severely 

damage it. 

 

Children and adolescents  

This medicine is not for children or adolescents under the age of 18 years because the safety and 

benefit of using ZALTRAP in children and adolescents have not been shown.  

 

Other medicines and ZALTRAP 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. This may include medicines obtained without a prescription or herbal medicines. 

 

Pregnancy, breast-feeding and fertility 

You should not use ZALTRAP during pregnancy unless you and your doctor decide that the benefit 

for you is greater than any possible risk to you or your unborn baby. 

If you are a woman that could become pregnant you should use effective contraception (see 

“Contraception” section below for details on male and female contraception). This medicine may harm 

your unborn baby since it may stop new blood vessels from forming. 

 

Talk to your doctor before being given this medicine if you are breast-feeding. This is because it is not 

known if the medicine passes into breast milk. 

 

ZALTRAP may affect male and female fertility. Talk to your doctor for advice if you plan to have or 

father a child. 

 

Contraception  

Men and women who can father or have children should use effective contraception: 

• during treatment with ZALTRAP and  

• for at least 6 months after the last dose of treatment. 
 

 

 



 

38 

Driving and using machines 

You may have side effects that affect your sight, concentration or ability to react. If this happens, do 

not drive or use any tools or machines. 

 

 

3. How ZALTRAP is given 

 

ZALTRAP will be given to you by a doctor or a nurse that is experienced in the use of 

‘chemotherapy’. It is given by a drip (infusion) into one of your veins (‘intra-venous’). ZALTRAP 

must not be injected into the eye, since it may severely damage it. 

 

The medicine must be diluted before it is given. Practical information for handling and administration 

of ZALTRAP for doctors, nurses and pharmacists when using this medicine is provided with this 

leaflet. 

 

How much and how often you will receive treatment 

• The drip (infusion) lasts for about 1 hour. 

• You will usually be given an infusion once every 2 weeks. 

• The recommended dose is 4 mg for each kilogram of your body weight. Your doctor will decide 
the correct dose for you. 

• Your doctor will decide how often you will be given the medicine and if you need a change in the 
dose. 

 

ZALTRAP will be given with other chemotherapy medicines including ‘5-fluorouracil’, ‘folinic acid’, 

and ‘irinotecan’. Your doctor will decide the appropriate doses for these other chemotherapy 

medicines. 

 

Treatment will continue as long as your doctor thinks the treatment is of benefit to you, and the side 

effects are acceptable.  

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

The side effects listed below were seen when ZALTRAP was given together with chemotherapy.  

 

Serious side effects 

 

Talk to your doctor straight away, if you notice any of the following serious side effects - you 

may need urgent medical treatment:  

• Bleeding: Very common (may affect more than 1 in 10 people) - this includes bleeding from the 
nose, but may also include severe bleeding in your gut and other parts of the body, which may lead 

to death. Signs may include feeling very tired, weak, and/or dizzy, or having changes in the colour 

of your stool. 

 

• Pain in the mouth, teeth and/or jaw, swelling or non-healing sores in the mouth or jaw, 

discharge, numbness or a feeling of heaviness in the jaw, or loosening of a tooth: Uncommon 

(may affect up to 1 in 100 people) - These symptoms could be signs of bone damage in the jaw 

(osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms while 

being treated with ZALTRAP or after stopping treatment. 

 

• Holes in the gut (also called ‘gastro-intestinal perforation’): Uncommon (may affect up to 1 in 
100 people) - this is a hole in the stomach, food pipe, gut or bowel. This can lead to death. Signs 

may include stomach pain, being sick (vomiting), fever or chills.  



 

39 

 

• Connections or passageways inside the body between internal organs and skin or other 
tissues (also called ‘fistula’): Common (may affect up to 1 in 10 people) - these abnormal 

tube-like connections or passageways can form for example, between the gut and your skin. 

Sometimes, depending on where this happens, you may get an unusual discharge at that place.  If 

you are uncertain contact your doctor.  

 

• High blood pressure (also called ‘hypertension’): Very common (may affect more than 1 in 10 
people) - this may develop or get worse. If blood pressure is not controlled, it may cause stroke, 

heart and kidney problems. Your doctor should check your blood pressure throughout your 

treatment. 

 

• Heart failure (also called cardiac failure); Uncommon (may affect up to 1 in 100 people) – Signs 
may include shortness of breath when you lie down or when you exert yourself, excessive 

tiredness or leg swelling.  

 

• Blocking of the arteries by a blood clot (also called ‘arterial thrombo-embolic events’): 
Common (may affect up to 1 in 10 people) - this may lead to a stroke or heart attack. Signs may 

include chest pain or heaviness in the chest, sudden numb or weak feeling in the face, arms, or 

legs. Other signs include feeling confused; problems with sight, walking, coordination or balance; 

or problems in saying words or slurring of speech. 

 

• Blocking of the veins by a blood clot (also called ‘venous thrombo-embolic events’): Common 
(may affect up to 1 in 10 people) - this may include a blood clot in the lungs or legs. Signs may 

include chest pain, coughing, being short of breath, difficulty breathing or coughing up blood. 

Other signs include swelling in one or both legs, pain or tenderness in one or both legs while 

standing or walking, warmth of the skin on the affected leg, red or discoloured skin in the affected 

leg or visible veins. 

 

• Protein in the urine (also called ‘proteinuria’): Very common (may affect more than 1 in 10 
people) – this is very commonly seen in tests. This may include swelling of the feet or whole body 

and may be related to kidney disease.  

 

• Low white blood cell count (also called ‘neutropenia’): Very common (may affect more than 1 
in 10 people) - this can cause serious infections. Your doctor will do blood tests regularly to check 

your white blood cell counts throughout your treatment. They may also prescribe a medicine 

called ‘G-CSF’ to help prevent complications if your white blood cell count is too low. Signs of 

infection may include fever, chills, cough, burning on passing water or muscle ache. You should 

take your temperature often during treatment with this medicine. 

 

• Diarrhoea and dehydration: Very common (may affect more than 1 in 10 people) for diarrhoea 
and Common (may affect up to 1 in 10 people) for dehydration - severe diarrhoea and being sick 

(vomiting) can cause you to lose too much body fluid (called ‘dehydration’) and body salts 

(electrolytes). Signs may include dizziness especially when going from sitting to standing. You 

may need to go to the hospital for treatment. Your doctor may give you medicines to stop or treat 

diarrhoea and being sick (vomiting). 

 

• Allergic reactions: Common (may affect up to 1 in 10 people) - these may happen within a few 
minutes after your infusion. Signs of allergic reaction may include rash or itching, skin redness, 

feeling dizzy or faint, being short of breath, tight chest or throat, or swelling of the face. Tell your 

doctor or nurse straight away if you have any of these signs during or soon after an infusion of 

ZALTRAP. 

 

• Wounds which heal slowly or not at all: Uncommon (may affect up to 1 in 100 people) - this is 
when a scar has trouble healing or staying closed, or if a healed wound re-opens. Your doctor will 

stop this medicine for at least 4 weeks before planned surgery and until the wound is fully healed. 



 

40 

 

• A side effect which affects your nervous system (called ‘posterior reversible encephalopathy 
syndrome’ or PRES): Uncommon (may affect up to 1 in 100 people) - signs may include 

headache, sight changes, feeling confused or fits with or without high blood pressure.  

 

Talk to your doctor straight away, if you notice any of the side effects above.  

 

Other side effects include: 

 

Very common (may affect more than 1 in 10 people) 

• drop in the number of white blood cells (leucopenia) 

• drop in the number of certain cells in the blood that help it to clot (thrombocytopenia) 

• decreased appetite 

• headache 

• nose bleeds 

• change of the voice, e.g. developing a hoarse voice 

• difficulty when breathing 

• painful sores in the mouth 

• stomach pain 

• swelling and numbness of the hands and feet that happens with chemotherapy (called 
‘Palmar-Plantar Erythrodysaesthesia syndrome’) 

• feeling tired or weak 

• weight loss  

• kidney problem with an increase in creatinine (a marker of kidney function) 

• liver problem with an increase in liver enzymes.  
 

Common (may affect up to 1 in 10 people) 

• urinary tract infection 

• inflammation inside the nose and upper part of the throat 

• pain in the mouth or throat 

• runny nose 

• haemorrhoids, bleeding or pain in the back passage 

• inflammation inside the mouth 

• toothache  

• changes in the colour of the skin. 
 

Uncommon (may affect up to 1 in 100 people) 

• an increase in protein in the urine, an increase in cholesterol in the blood, and swelling from 
excess fluid (oedema) (also called ‘nephrotic syndrome’) 

• blood clot in very small blood vessels (also called ‘thrombotic microangiopathy’). 
 

Not known (frequency cannot be estimated from the available data) 

• an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 
and artery dissections) 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store ZALTRAP 

 

Keep this medicine out of the sight and reach of children. 

http://encyclopedia.thefreedictionary.com/Chemotherapy
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

41 

 

Do not use this medicine after the expiry date which is stated on the outer carton and on the label of 

the vial after EXP. The expiry date refers to the last day of that month. 

 

Store in a refrigerator (2°C - 8°C). 

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

 

Information about storage and the time to use ZALTRAP, after it has been diluted and is ready to use, 

is described in the ‘Practical information for healthcare professionals on preparation and handling of 

ZALTRAP 25 mg / ml concentrate for solution for infusion’ at the end of this leaflet.  

 

Do not use ZALTRAP if you notice particles or discolouration of the medicine in the vial or infusion 

bag. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What ZALTRAP contains  

• The active substance is aflibercept. One ml of concentrate contains 25 mg aflibercept. One 4 ml 
vial of concentrate contains 100 mg aflibercept. One 8 ml vial of concentrate contains 200 mg 

aflibercept. 

• The other ingredients are: 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 and water for injections.  

 

What ZALTRAP looks like and contents of the pack 

ZALTRAP is a concentrate for solution for infusion (sterile concentrate). The concentrate is a clear, 

colourless to pale yellow solution. 

• 4 ml of concentrate in a 5 ml clear borosilicate glass vial (type I), sealed by a flanged stopper with 
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 stopper 
with flip-off cap and inserted coated sealing disc. Pack size of 1 vial. 

 

Not all pack sizes may be marketed.  

 

Marketing Authorisation Holder  

sanofi-aventis groupe 

54, rue La Boétie 

75008 Paris 

France 

 

Manufacturer 

Sanofi-Aventis Deutschland GmbH 

Industriepark Hoechst 

65926 Frankfurt am Main 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 



 

42 

België/Belgique/Belgien 

Sanofi Belgium 

Tél/Tel: +32 (0)2 710 54 00 

 

Lietuva 

UAB “SANOFI-AVENTIS LIETUVA” 

Tel: +370 5 2755224 

 

България 

sanofi-aventis Bulgaria EOOD 

Тел.: +359 (0)2 970 53 00 

 

Luxembourg/Luxemburg 

Sanofi Belgium  

Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 

 

Česká republika 

sanofi-aventis, s.r.o. 

Tel: +420 233 086 111 

 

Magyarország 

SANOFI-AVENTIS zrt.  

Tel.: +36 1 505 0050 

 

Danmark 

Sanofi A/S 

Tlf: +45 45 16 70 00 

 

Malta 

Sanofi S.p.A 

Tel: +39 02 39394275 

 

Deutschland 

Sanofi-Aventis Deutschland GmbH 

 

Tel.: 0800 04 36 996 

Tel. aus dem Ausland: +49 69 305 70 13 

 

 

Nederland 

sanofi-aventis Netherlands B.V. 

Tel: +31 (0)20 245 4000 

 

 

Eesti 

sanofi-aventis Estonia OÜ 

Tel: +372 627 34 88 

 

Norge 

sanofi-aventis Norge AS 

Tlf: +47 67 10 71 00 

 

Ελλάδα 

sanofi-aventis AEBE 

Τηλ: +30 210 900 16 00 

 

Österreich 

sanofi-aventis GmbH 

Tel: +43 1 80 185 – 0 

 

España 

sanofi-aventis, S.A. 

Tel: +34 93 485 94 00 

 

Polska 

sanofi-aventis Sp. z o.o. 

Tel.: +48 22 280 00 00 

 

France 

sanofi-aventis France 

Tél: 0 800 222 555 

Appel depuis l’étranger : +33 1 57 63 23 23 

Portugal 

Sanofi - Produtos Farmacêuticos, Lda. 

Tel: +351 21 35 89 400 

Hrvatska 

sanofi-aventis Croatia d.o.o. 

Tel: +385 1 600 34 00 

România 

Sanofi Romania SRL 

Tel: +40 (0) 21 317 31 36 

 

Ireland 

sanofi-aventis Ireland Ltd. T/A SANOFI 

Tel: +353 (0) 1 403 56 00 

 

Slovenija 

sanofi-aventis d.o.o. 

Tel: +386 1 560 48 00 

 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

sanofi-aventis Pharma Slovakia s.r.o. 

Tel: +421 2 33 100 100 

 

Italia 

Sanofi S.p.A. 

Tel: + 39 059 349 811 

 

Suomi/Finland 

Sanofi Oy 

Puh/Tel: +358 (0) 201 200 300 

 



 

43 

Κύπρος 

sanofi-aventis Cyprus Ltd. 

Τηλ: +357 22 871600 

 

Sverige 

Sanofi AB 

Tel: +46 (0)8 634 50 00 

 

Latvija 

sanofi-aventis Latvia SIA 

Tel: +371 67 33 24 51 

 

United Kingdom 

Sanofi 

Tel: +44 (0) 845 372 7101 

 

 

This leaflet was last revised in  

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu  

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


 

44 

-------------------------------------------------------------------------------------------------------------------------- 

 

The following information is intended for healthcare professionals only: 

 

PRACTICAL INFORMATION FOR HEALTHCARE PROFESSIONALS 

ON PREPARATION AND HANDLING OF ZALTRAP 25 mg / ml CONCENTRATE FOR 

SOLUTION FOR INFUSION 

 

This information supplements the sections 3 and 5 for the user. 

It is important that you read the entire content of this procedure prior to the preparation of infusion 

solution. 

 

ZALTRAP is a sterile, preservative-free and non-pyrogenic concentrate, therefore the solution for 

infusion should be prepared by a healthcare professional using safe-handling procedures and aseptic 

technique. 

Caution should be exercised when handling ZALTRAP, taking into account the use of containment 

devices, 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 and 

without particles.  

• Based on the required dose for the patient, withdraw the necessary volume of ZALTRAP 
concentrate from the vial. More than one vial could be needed for the preparation of the infusion 

solution.  

• Dilute it to the required administration volume with sodium chloride 9 mg / ml (0.9 %) solution 
or 5 % glucose solution for infusion. The concentration of the final ZALTRAP solution for 

intravenous 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 discolouration 

prior to administration. If any discolouration or particulate matter is observed, the 

reconstituted solution should be discarded. 

• ZALTRAP is a single-use vial. Do not re-enter the vial after the initial puncture. Any unused 

concentrate should be discarded. 

 

Shelf-life 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 for 

8 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 the 

user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in 

controlled and validated aseptic conditions. 

 

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 section 2 of the package leaflet). 

 

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

 

Diluted solutions of ZALTRAP should be administered using infusion sets containing a 0.2 micron 

polyethersulfone filter. 

 



 

45 

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.   

 

Disposal 

Any unused medicine or waste material should be disposed of in accordance with local requirements. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS
	ANNEX II
	MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT

	ANNEX III
	A. LABELLING
	B. PACKAGE LEAFLET