aflibercept: package leaflet

the blister ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready for assembly.

hand while using the other hand to grasp the syringe cap with the thumb and fore finger. Please note:
You should twist off (do not snap off) the syringe cap.

needle onto the Luer-lock syringe tip.

check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.

7.

Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger to align the base of the plunger dome (not the tip of the dome) with the dosing line on the syringe (equivalent to 0.05 mL i.e. 2 mg aflibercept).

Note: This accurate positioning of the plunger is very important, because incorrect plunger positioning can lead to delivering more or less than the labelled dose

8. Inject while pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. Do not administer any residual solution observed in the syringe.
9.
The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Eylea is a solution which is injected into the eye. Eylea belongs to a group of medicines called antineovascularisation agents. It contains the active substance called aflibercept.

Eylea is used in babies born prematurely to treat an eye condition called retinopathy of prematurity (ROP). Babies with ROP have abnormal growth of new blood vessels in the back of the eye (retina) induced by Vascular Endothelial Growth Factor (VEGF). This may cause vision impairment and in severe cases permanent blindness.

Aflibercept, the active substance in Eylea, blocks the activity of a group of factors, known as Vascular Endothelial Growth Factor A (VEGF-A) and Placental Growth Factor (PlGF).

Eylea has been shown to stop the growth of new abnormal blood vessels in the eye which often leak fluid or bleed. Eylea can help to stabilise, and in many cases, improve the vision loss related to ROP.

The baby will not be given Eylea if he or she
- is allergic to aflibercept or any of the other ingredients of this medicine (listed in section 6).
- has an active or suspected infection in or around the eye (ocular or periocular infection).
- has severe inflammation of the eye (indicated by pain or redness).

Warnings and precautions
Talk to the baby’s doctor before the baby is given Eylea
- if surgery was performed or is planned on the baby’s eye within the previous or next four weeks.

Furthermore, it is important for you to know that

- injections with Eylea may cause an increase in eye pressure (intraocular pressure) in some patients within 60 minutes of the injection. The baby’s doctor will monitor this after each injection.
- if the baby develops an infection or inflammation inside the eye (endophthalmitis) or other complications, the baby may have redness/irritation of the eye, ocular discharge, lid swelling and increased sensitivity to light. It is important to have any symptoms diagnosed and treated as soon as possible.
Please tell the baby’s doctor immediately if the baby develops any signs or symptoms outlined.
- the baby’s doctor will check whether the baby has other risk factors that may increase the chance of a tear or detachment of one of the layers at the back of the eye (retinal detachment or tear), in which case Eylea must be given with caution.

The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea into the eye.

There is no experience in the treatment of
- patients with acute infections
- patients with other eye conditions such as a detachment of the retina or a hole in the macula

If any of the above applies to the baby, the baby’s doctor will consider this lack of information when treating the baby with Eylea.

Other medicines and Eylea
Tell the baby’s doctor if the baby is receiving, has recently received or might receive any other medicines.

Eylea contains
- less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free’.
- 0.003 mg of polysorbate 20 in each 0.01 ml dose which is equivalent to 0.3 mg/ml. Polysorbates may cause allergic reactions. Tell your doctor if your baby has any known allergies.

A doctor experienced in giving eye injections will inject Eylea into the baby’s eyes under aseptic (clean and sterile) conditions.

The recommended dose is 0.4 mg aflibercept (0.01 mL).
Eylea is given as an injection into the baby’s eye (intravitreal injection).

Before the injection the baby’s doctor will use a disinfectant eyewash to clean the baby’s eye carefully to prevent infection. The baby’s doctor will also give the baby a local anaesthetic to reduce or prevent any pain the baby might have with the injection.

The treatment is started with a single injection per eye and may be given into the second eye on the same day. The baby’s doctor will monitor the condition of the baby’s eye(s). Depending on how the baby responds to the treatment, the baby’s doctor will decide if and when further treatment is needed.
The treatment interval between the 2 doses injected into the same eye should be at least 4 weeks.

Detailed instructions for use are given at the end of the leaflet under “How to prepare and administer Eylea to preterm infants”.

Stopping treatment with Eylea
If you are considering stopping Eylea treatment for the baby, please discuss this with the baby’s doctor at your next appointment. The baby’s doctor will advise you and decide how long the baby should be treated with Eylea.

If you have any further questions on the use of this medicine, ask the baby’s doctor.

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

Side effects reported in more than one baby born prematurely were
- detachment of the layer in the back of the eye (retinal detachment)
- bleeding in the back of the eye (retinal haemorrhage)
- bloodshot eye caused by bleeding from small blood vessels in the outer layers of the eye (conjunctival haemorrhage)
- bleeding at the injection site (injection site haemorrhage)
- increase in eye pressure
- swelling of the eyelid (eyelid oedema)

Additional side effects that have been observed with Eylea in adults are listed below. These side effects may also occur in babies born prematurely
- allergic reactions (hypersensitivity)
These may be serious and require that you contact the baby’s doctor immediately.

Side effects affecting the eyes due to the injection procedure may be serious and include
- blindness
- a serious infection or inflammation inside the eye (endophthalmitis)
- detachment, tear or bleeding of the light-sensitive layer at the back of the eye (retinal detachment or tear)
- clouding of the lens (cataract)
- bleeding in the eye (vitreous haemorrhage)
- detachment of the gel-like substance inside the eye from the retina (vitreous detachment)
- increase of pressure inside the eye (intraocular pressure increased), see section 2 These serious side effects affecting the eyes occurred in less than 1 in 1,900 injections in clinical studies in adults.

It is important to identify and treat serious side effects such as infection inside the eye or retinal detachment as soon as possible.
Tell the baby’s doctor immediately if you notice symptoms in the baby’s eye after injection such as
- redness/irritation
- ocular discharge
- lid swelling
- increased sensitivity to light

Other side effects observed in adults are described below.

List of side effects reported
The following is a list of the side effects reported to be possibly related to the injection procedure or to the medicine. Please do not get alarmed, the baby might not experience any of these. Always discuss any suspected side effects with the baby’s doctor.

Very common side effects (may affect more than 1 in 10 people):
- deterioration of eyesight
- bleeding in the back of the eye (retinal haemorrhage)
- bloodshot eye caused by bleeding from small blood vessels in the outer layers of the eye
- eye pain

Common side effects (may affect up to 1 in 10 people):
- detachment or tear of one of the layers in the back of the eye, resulting in flashes of light with floaters sometimes progressing to a loss of vision (retinal pigment epithelial tear*/detachment, retinal detachment/tear) o * Conditions known to be associated with wet age-related macular degeneration (AMD);
observed in wet AMD patients only.
- degeneration of the retina causing disturbed vision
- bleeding in the eye (vitreous haemorrhage)
- certain forms of clouding of the lens (cataract)
- damage to the front layer of the eyeball (the cornea)
- increase in eye pressure
- moving spots in vision (floaters)
- detachment of the gel-like substance inside the eye from the retina (vitreous detachment, resulting in flashes of light with floaters)
- a feeling of having something in the eye
- increased tear production
- swelling of the eyelid
- bleeding at the injection site
- redness of the eye

Uncommon side effects (may affect up to 1 in 100 people):
- allergic reactions (hypersensitivity)** o ** Allergic reactions like rash, itching (pruritus), hives (urticaria), and a few cases of severe allergy (anaphylactic/anaphylactoid) reactions were reported.
- serious inflammation or infection inside the eye (endophthalmitis)
- inflammation in the iris or other parts of the eye (iritis, uveitis, iridocyclitis, anterior chamber flare)
- abnormal sensation in the eye
- eyelid irritation
- swelling of the front layer of the eyeball (cornea)

Rare side effects (may affect up to 1 in 1,000 people):
- blindness
- clouding of the lens due to injury (traumatic cataract)
- inflammation of the gel-like substance inside the eye
- pus in the eye
- inflammation of blood vessels in the back of the eye (retinal vasculitis)

Not known (frequency cannot be estimated from the available data):
- inflammation of the white part of the eye associated with redness and pain (scleritis)
- blockage of blood vessels in the back of the eye, typically in presence of inflammation (retinal occlusive vasculitis)

The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea into the eye.

As with all therapeutic proteins, there is a possibility for an immune reaction (formation of antibodies) with Eylea.

If you have any questions about any side effects, ask the baby’s doctor.

Reporting of side effects
If you observe any side effects in the baby, talk to the baby’s doctor. 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.

- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and label after EXP.
The expiry date refers to the last day of that month.
- Store in a refrigerator (2 °C to 8 °C). Do not freeze.
- The unopened blister may be stored outside the refrigerator below 25 ºC for up to 24 hours.
- Store in the original package in order to protect from light.
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away any medicines you no longer use. These measures will help protect the environment.

What Eylea contains
- The active substance is: aflibercept. One pre-filled syringe contains an extractable volume of at least 0.09 mL, equivalent to at least 3.6 mg aflibercept. One pre-filled syringe delivers a single dose of 0.4 mg aflibercept in 0.01 mL.
- The other ingredients are: polysorbate 20 (E 432), sodium dihydrogen phosphate monohydrate (for pH adjustment), disodium hydrogen phosphate heptahydrate (for pH adjustment), sodium chloride, sucrose, water for injections.

See ‘Eylea contains’ in section 2 for more information.

What Eylea looks like and contents of the pack
Eylea is a solution for injection (injection) in a pre-filled syringe. The solution is colourless to pale yellow.
Pack size of 1 pre-filled syringe.

Marketing Authorisation Holder
Bayer AG
51368 Leverkusen
Germany

Manufacturer

Bayer AG
Müllerstraße 178
13353 Berlin
Germany

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

België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Lietuva
UAB Bayer
Tel: +370-5-233 68 68
България
Байер България ЕООД
Тел: +359-(0)2-424 72 80
Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Česká republika
Bayer s.r.o.
Tel: +420-266 101 111
Magyarország
Bayer Hungária KFT
Tel: +36-1-487 4100
Danmark
Bayer A/S
Tlf: +45-45 235 000
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Nederland
Bayer B.V.
Tel: +31-23-799 1000
Eesti
Bayer OÜ
Tel: +372-655 85 65
Norge
Bayer AS
Tlf: +47-23 13 05 00
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30-210-618 75 00
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 460
España
Bayer Hispania S.L.
Tel: +34-93-495 65 00
Polska
Bayer Sp. z o.o.
Tel: +48-22-572 35 00
France
Bayer HealthCare
Tél (N° vert): +33-(0)800 87 54 54
Portugal
Bayer Portugal, Lda.
Tel: +351-21-416 42 00
Hrvatska
Bayer d.o.o.
Tel: + 385-(0)1-6599 900
România
SC Bayer SRL
Tel: +40-(0)21-529 59 00
Ireland
Bayer Limited
Tel: +353-(0)1-216 3300
Slovenija
Bayer d. o. o.
Tel: +386-(0)1-58 14 400
Ísland
Icepharma hf.
Sími: +354-540 80 00
Slovenská republika
Bayer, spol. s r.o.
Tel: +421-(0)2-59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-3978 1
Suomi/Finland
Bayer Oy
Puh/Tel: +358-(0)20-78521
Κύπρος
NOVAGEM Limited
Τηλ: +357-22-48 38 58
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIA Bayer
Tel: +371-67 84 55 63

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:
https://www.ema.europa.eu.

For local information scan here to access the website https://www.pi.bayer.com/eylea1.
QR-code carrying the link to package leaflet included.

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The following information is intended for healthcare professionals only:

How to prepare and administer Eylea to preterm infants

The pre-filled syringe should only be used for the treatment of a single eye. Extraction of multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

Do not open the sterile pre-filled blister outside the clean administration room. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The pre-filled syringe contains more than the recommended dose of 0.4 mg aflibercept (equivalent to 0.01 mL). For treatment of preterm infants, the PICLEO paediatric dosing device in combination with the pre-filled syringe must be used for administration of a single dose of 0.4 mg aflibercept (equivalent to 0.01 mL). See following section “Instructions for use of pre-filled syringe”.

The solution should be inspected visually for any foreign particulate matter and/or discolouration or any variation in physical appearance prior to administration. In the event of either being observed, discard the medicinal product.

The unopened blister may be stored outside the refrigerator below 25 ºC for up to 24 hours. After opening the blister, proceed under aseptic conditions.
For the intravitreal injection, a 30 G x ½ inch injection needle should be used.

Instructions for use of pre-filled syringe:
To prepare the pre-filled syringe for administration to preterm infants, follow the steps 1 and 2 below and then adhere to the instructions for use included in the package of the PICLEO paediatric dosing device.

1.
When ready to administer Eylea, open the carton and remove the sterilised blister. Carefully peel open the blister ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready for assembly.
2.
Using aseptic technique, remove the syringe from the sterilised blister.

the rubber stopper of the vial.

carton to a 1 mL sterile Luer-lock syringe.

the vial and the tip touches the bottom or bottom edge of the vial.

contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal.
To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.

empty the filter needle.

Note: Filter needle is not to be used for intravitreal injection.

7.
Using aseptic technique, firmly twist a 30 G x ½ inch injection needle onto the Luer-lock syringe tip.

8.
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
9.
Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger so that the flat plunger edge aligns with the line that marks 0.05 mL on the syringe.

10.
The vial is for single use only. Extraction of multiple doses from a single vial may increase the risk of contamination and subsequesnt infection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not use the vial if particulates, cloudiness, or discolouration are visible.

outer part of the rubber stopper of the vial.

Attach the filter needle supplied in the carton to a 1-ml sterile, Luer-lock syringe.

into the vial and the tip touches the bottom or bottom edge of the vial.

slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.

empty the filter needle. After injection any unused product must be discarded.
7.
Remove the filter needle and properly dispose of it.
Note: The filter needle is not to be used for the intravitreal injection.
8.
Firmly twist the 30 G × ½ inch injection needle onto the Luer-lock syringe tip.
9.
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
needle bevel pointing down solution

10.
To eliminate all bubbles and to expel excess medicinal product, slowly depress the plunger so that the flat plunger edge aligns with the line that marks 0.07 ml on the syringe.

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

solution after expelling air bubbles and excess medicinal product dose line for
0.07 ml flat plunger edge

When ready to administer Eylea 114.3mg/ml, open the carton and remove the sterile blister.
Carefully peel open the blister ensuring the sterility of its contents.
Keep the syringe in the sterile tray until you are ready to attach the injection needle.

Use aseptic technique to carry out steps 2-9.

Remove the syringe from the sterilised blister.

syringe cap
Luer-lock plunger stopper
OcuClick dosing system finger grip plunger rod guide
90° view slot

Do not use the pre-filled syringe if
- particulates, cloudiness, or discolouration are visible
- any part of the pre-filled syringe with OcuClick dosing system is damaged or loose
- the syringe cap is detached from the Luer-lock.

To snap off (do not twist off) the syringe cap, hold the syringe in one hand and the syringe cap with the thumb and forefinger of the other hand.
Note: Do not pull back on the plunger rod.

Firmly twist the 30 G × ½ inch injection needle onto the Luer-lock syringe tip.

SNAP!
Luer-lock

Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
7.
Expel air and excess volume to prime
The syringe does not have a dose line because it is designed to set the dose mechanically as explained in the steps below.

Priming and setting the dose must be done using the following steps.
To eliminate all bubbles and to expel excess medicinal product, slowly depress the plunger rod (left picture below) until it stops, i.e. when the guide on the plunger rod reaches the finger grip (right picture below).
8.
Set the dose

TAP!
plunger rod guide
Ensure bubbles are at the top so they can be expelled.
finger grip air bubble solution finger grip plunger rod guide fully depressed plunger

Turn the end of the plunger rod 90 degrees clockwise or counter clockwise until the guide of the plunger rod aligns with the slot. You may hear a ‘click’.
Note: Now the device is ready to dose. Do not push the plunger rod before insertion into the eye.
9.
Administer the injection

Insert the needle into the ocular injection site.
Inject the solution by pushing in the plunger rod until it stops, i.e. until the guide is completely within the slot.

Do not apply additional pressure once the guide is within the slot. It is normal to see a small amount of residual solution left in the syringe.
10. The pre-filled syringe is for single dose administration and single use only.
After injection discard the used syringe into a sharps container.

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

guide plunger rod slot
CLICK!
guide plunger rod slot

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATION(S)

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for aflibercept (ophthalmological indication(s)), the scientific conclusions of PRAC are as follows:

In view of available data on retinal vasculitis with or without occlusion from clinical trials, the literature, spontaneous reports and in view of a plausible mechanism of action, the PRAC considers a causal relationship between aflibercept and retinal vasculitis with or without occlusion, is at least a reasonable possibility.

The PRAC concluded that the product information of products containing aflibercept (all formulation) should be amended accordingly.

Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions and grounds for recommendation.

Grounds for the variation to the terms of the Marketing Authorisation(s)

On the basis of the scientific conclusions for aflibercept (ophthalmological indication(s)) the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing aflibercept (ophthalmological indication(s)) is unchanged subject to the proposed changes to the product information.

The CHMP recommends that the terms of the Marketing Authorisation(s) should be varied.

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’.

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.

• 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.

• 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 must use effective contraception (see “Contraception” section below for details on 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
Women who can have children must use effective contraception:
- during treatment with ZALTRAP and
- for 3 months after the last dose of treatment.

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.

ZALTRAP contains sodium
This medicine contains up to 22 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 1.1% of the recommended maximum daily dietary intake of sodium for an adult.

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.

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.

- 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.

• 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.

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

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.

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 Winthrop Industrie
82 avenue Raspail
94250 Gentilly
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:

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

Lietuva
Swixx Biopharma UAB
Tel: +370 5 236 91 40

България
Swixx Biopharma EOOD
Тел.: +359 (0)2 4942 480

Luxembourg/Luxemburg
Sanofi Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)

Česká republika
Sanofi 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.r.l.
Tel: +39 02 39394275

Deutschland
Sanofi-Aventis Deutschland GmbH

Tel.: 0800 52 52 010
Tel. aus dem Ausland: +49 69 305 21 131

Nederland
Sanofi B.V.
Tel: +31 (0)20 245 4000

Eesti
Swixx Biopharma OÜ
Tel: +372 640 10 30

Norge sanofi-aventis Norge AS
Tlf: +47 67 10 71 00

Ελλάδα
Sanofi-Aventis Μονοπρόσωπη 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 Sp. z o.o.
Tel.: +48 22 280 00 00

France
Sanofi Winthrop Industrie
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
Swixx Biopharma d.o.o.
Tel: +385 1 2078 500
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
Swixx Biopharma d.o.o.
Tel: +386 1 235 51 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Swixx Biopharma s.r.o.
Tel: +421 2 208 33 600

Italia
Sanofi S.r.l.
Tel: 800536389

Suomi/Finland
Sanofi Oy
Puh/Tel: +358 (0) 201 200 300

Κύπρος
C.A. Papaellinas Ltd.
Τηλ: +357 22 741741

Sverige
Sanofi AB
Tel: +46 (0)8 634 50 00

Latvija
Swixx Biopharma SIA
Tel: +371 6 616 47 50

United Kingdom (Northern Ireland) sanofi-aventis Ireland Ltd. T/A SANOFI
Tel: +44 (0) 800 035 2525

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

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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.

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.