Leaflet: information for the user

ZALTRAP 25 mg/ml concentrate for solution for infusion

Aflibercept

Read this leaflet carefully before you start using this medicine,because it contains important information for you.

• Keep this leaflet, as you may need to read it again or give it to healthcare professionals in the future.
• If you have any questions, consult your doctor, pharmacist or nurse.
• If you experience any side effects,consult your doctor, pharmacist or nurse,evenif they do not appear in this leaflet. See section 4.

1. What is ZALTRAP and what it is used for

2. What you need to know before starting to use ZALTRAP

3. How to use ZALTRAP

4. Possible side effects

5. Storage of ZALTRAP

6. Contents of the pack and additional information

What is ZALTRAP and how it works

ZALTRAP contains the active ingredient aflibercept, a protein that acts by blocking the growth of new blood vessels within the tumor. The tumor needs nutrients and oxygen from the blood to grow. By blocking the growth of blood vessels, ZALTRAP helps to stop or slow down the growth of the tumor.

How ZALTRAP is used

ZALTRAP is a medication used to treat advanced colon or rectal cancer (parts of the large intestine) in adults. It will be administered along with other medications called “chemotherapeutic agents”, including “5-fluorouracil”, “folinic acid” and “irinotecan”.

Do not use ZALTRAP

• if you are allergic to aflibercept or any of the other ingredients in this medicine (listed in section 6);
• in your eyes, as it could severely damage them.

Also read the leaflets for other medicines (“chemotherapy”) that are part of your treatment, to check if they are suitable for you. If you are unsure, consult your doctor, pharmacist or nurse if there is any reason why you cannot use these medicines.

Warnings and precautions

Consult your doctor, pharmacist or nurse before and during treatment with ZALTRAP if:

• you have bleeding problems or experience any bleeding after treatment (see section 4), or if you notice extreme tiredness, weakness, dizziness, or a change in the colour of your stools. If 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 (gingivitis), or a planned tooth extraction, and especially if you have been treated before with bisphosphonates (used to treat or prevent problems in your bones). There have been reports of an adverse effect called osteonecrosis (bone damage in the jaw) in cancer patients treated with ZALTRAP. You may be advised to have a dental check-up before starting treatment with ZALTRAP. While you are being treated with ZALTRAP, you must maintain good oral hygiene (including regular brushing of your teeth) and have regular dental check-ups. If you have dentures, you must ensure they are securely fixed. If you have previously received or are receiving treatment with bisphosphonates intravenously, avoid dental treatments or dental surgery (e.g. tooth extraction). Inform your doctor about your dental treatments 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 in your mouth or teeth, such as tooth loss, pain, or inflammation, or ulcers that do not heal or discharge, as these may be symptoms of osteonecrosis of the jaw.

• you have conditions in which your intestine is inflamed, such as infection in a part of the intestinal wall (also known as “diverticulitis”), stomach ulcers, or colitis. This is because ZALTRAP may increase the risk of developing perforations in the intestinal wall. If this happens, your doctor will stop your treatment with ZALTRAP.

• you have developed abnormal connections, such as tubes or channels, within your body between internal organs and the skin and other tissues (also known as “fistulas”). If you develop this type of connection or channel during treatment, your doctor will stop the treatment with ZALTRAP.

• you have high blood pressure. ZALTRAP may increase blood pressure (see section 4), and your doctor will need to control your blood pressure and may adjust the dose of your blood pressure medicines or your dose of ZALTRAP. Therefore, it is essential to inform your doctor, pharmacist, or nurse if you have other heart problems, as blood pressure may worsen.

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

• you experience shortness of breath when exerting yourself or when lying down, excessive tiredness, or leg inflammation, which may be symptoms of heart failure.

• you experience signs of a blood clot (see section 4). Signs of a blood clot may vary, depending on where it occurs (e.g. lungs, legs, heart, or brain), but may include symptoms such as chest pain, coughing, shortness of breath, or difficulty breathing. Other signs may include leg inflammation, pain, or sensitivity in one or both legs, skin discoloration and warmth in the affected leg, or visible veins. It may also present as a sudden feeling of numbness or weakness in the face, arms, or legs. Other symptoms include confusion, vision problems, walking difficulties, coordination or balance problems, speech difficulties, or difficulty speaking. If you experience any of these symptoms, inform your doctor immediately, as your doctor may want to treat your symptoms and stop treatment with ZALTRAP.

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

• your white blood cell count is too low. ZALTRAP may reduce your white blood cell count, and your doctor will monitor your white blood cell count and may administer other medicines to increase it. If your white blood cell count is low, your doctor may need to delay treatment.

• you have severe or persistent diarrhea, feel unwell (nausea), or are vomiting – this can cause severe fluid loss (called “dehydration”). Your doctor may need to treat you with other medicines and/or administer intravenous fluids.

• you have had allergies in the past – during treatment with ZALTRAP, severe allergic reactions may occur (see section 4). Your doctor may need to treat the allergic reaction or stop treatment with ZALTRAP.

• you have had a tooth extraction or have undergone surgery in the past 4 weeks, or are about to undergo an operation or medical or dental intervention, or have a wound from a previous operation that has not yet healed. Your doctor will temporarily stop treatment before and after surgery.

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

• you are 65 years or older and experience diarrhea, dizziness, weakness, weight loss, or lose a large amount of fluid (called “dehydration”). Your doctor will closely monitor you.

• your daily activities are limited or worsen during treatment. Your doctor will closely monitor you.

If you are in any of the above situations (or are unsure), inform your doctor, pharmacist, or nurse before you are given ZALTRAP and during treatment.

During treatment, your doctor will perform various tests to monitor your body's function and how the medicine works. The tests may include blood and urine analyses, X-rays, or other imaging techniques and/or other tests.

ZALTRAP is administered through a drip (infusion) into one of your veins (intravenously) to treat advanced cancers of the colon or rectum. ZALTRAP should not be injected into the eyes, as it could severely damage them.

Children and adolescents

This medicine is not for children or adolescents under 18 years, as it has not been shown to be safe and effective in children and adolescents.

Use of ZALTRAP with other medicines

Inform your doctor, pharmacist, or nurse if you are using, have used recently, or may need to use any other medicine. This may include medicines bought without a prescription or herbal medicines.

Pregnancy, breastfeeding, and fertility

You should not use ZALTRAP during pregnancy, unless your doctor decides that the benefits for you outweigh any possible risks for you or your baby.

If you can become pregnant, you must use an effective contraceptive method (see the section “Contraception” below for details on contraception in women). This medicine may harm the fetus, as it prevents the formation of new blood vessels.

If you are breastfeeding, consult your doctor before you are given this medicine. This is because it is not known whether the medicine passes into breast milk.

ZALTRAP may affect the fertility of men and women. Consult your doctor for advice if you plan to have a child.

Contraception

Women who can become pregnant must use an effective contraceptive method:

• during treatment with ZALTRAP and
• for 3 months after the last dose of treatment.

Driving and operating machinery

You may experience adverse effects that affect your vision, concentration, or reaction time. If this occurs, do not drive or use tools or machinery.

ZALTRAP contains sodium

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

ZALTRAP will be administered by a doctor or nurse experienced in the use of “chemotherapy”. It is administered by infusion (intravenous) into one of your veins. ZALTRAP cannot be injected into your eyes, as it could severely damage them.

The medication must be diluted before administration. Practical information on the handling and administration of ZALTRAP for doctors, nurses, and pharmacists when using this medication is included in this prospectus.

How much and how often you will receive treatment

• The infusion lasts around 1 hour.
• You will normally receive an infusion once every 2 weeks.
• The recommended dose is 4 mg per kilogram of body weight. Your doctor will decide what the correct dose is for you.
• Your doctor will decide how often you will receive the medication and if you need any changes to the dose.

ZALTRAP will be administered with other chemotherapy medications, including “5-fluorouracil”, “folic acid” and “irinotecan”. Your doctor will decide on the appropriate doses of these other chemotherapy medications.

Treatment will continue until your doctor believes it is beneficial for you and the side effects are acceptable.

If you have any further questions about the use of this medication, consult your doctor, pharmacist or nurse.

Like all medicines, ZALTRAP can cause side effects, although not everyone will experience them. The side effects listed below were observed when ZALTRAP was administered with chemotherapy:

Severe side effects

Inform your doctor immediately if you notice any of the following severe side effects – you may need urgent medical treatment:

• Bleeding:Very common(may affect more than 1 in 10 people) – this includes nasal bleeding, but may also include severe bleeding in your intestines and other parts of your body that can be life-threatening. Symptoms include feeling extremely tired, weak, or dizzy, or changes in your stool color.

• Mouth, tooth, or jaw pain, inflammation, or ulcers that do not heal in your mouth or jaw, discharge, numbness, or a feeling of heaviness in your jaw, or tooth loss:Uncommon(may affect up to 1 in 100 people) – these symptoms may be signs of jaw bone damage (osteonecrosis). Inform your doctor and dentist immediately if you experience these symptoms while being treated with ZALTRAP, or after stopping treatment.

• Intestinal perforation:Uncommon(may affect up to 1 in 100 people) – this is a hole in your stomach, esophagus, small intestine, or large intestine. It can be life-threatening. Symptoms include stomach pain, discomfort (vomiting), fever, or chills.

• Abnormal connections or channels within your body between internal organs and the skin or other tissues (also called "fistulas"):Common(may affect up to 1 in 10 people) – these abnormal connections similar to tubes or channels may form, for example, between your intestine and skin. Sometimes, depending on where they occur, you may have abnormal flow in that area. If you are unsure, consult your doctor.

• High blood pressure:Very common(may affect more than 1 in 10 people) – it may develop or worsen. If blood pressure is not controlled, it can cause stroke and heart and kidney problems. Your doctor should monitor your blood pressure during treatment.

• Heart failure (also called congestive heart failure):Uncommon(may affect up to 1 in 100 people) – symptoms may include shortness of breath when lying down or exerting yourself, excessive tiredness, or leg swelling.

• Blockage of arteries by a blood clot (also called arterial thromboembolic events):Common(may affect up to 1 in 10 people) – this can cause a stroke or heart attack. Symptoms may include chest pain or pressure, sudden numbness or weakness in the face, arm, or leg, confusion, vision problems, walking difficulties, coordination or balance problems, or difficulty speaking or slurred speech.

• Blockage of veins by a blood clot (also called venous thromboembolic events):Common(may affect up to 1 in 10 people) – it may include a clot in your lungs or legs. Symptoms may include chest pain, coughing, shortness of breath, difficulty breathing, or coughing up blood. Other symptoms may include leg swelling, pain or sensitivity in one or both legs, either at rest or when walking, warmth in the affected leg skin, red or discolored skin in the affected leg, or visible veins.

• Protein in the urine:Very common(may affect more than 1 in 10 people) – this is observed very frequently in tests. It may include leg or whole body swelling and may be related to kidney damage.

• Low white blood cell count (also called neutropenia):Very common(may affect more than 1 in 10 people) – it may cause severe infections. Your doctor will perform regular blood tests to monitor your white blood cell count during treatment. They may also prescribe a medication called "G-CSF" to help prevent complications if your white blood cell count is too low. Symptoms of infection may include fever, chills, cough, burning sensation while urinating, or muscle pain. During treatment with this medication, you should take your temperature often.

• Dysuria and dehydration:Very common(may affect more than 1 in 10 people) for diarrhea andCommon(may affect up to 1 in 10 people) for dehydration – severe diarrhea and discomfort (vomiting) may cause you to lose a lot of fluid (which is called "dehydration") and salts from your body (electrolytes). Symptoms may include dizziness, especially when standing up. You may need hospital treatment. Your doctor will administer medications to stop or treat diarrhea and discomfort (vomiting).

• Allergic reactions: Common(may affect up to 1 in 10 people) – they may occur a few minutes after infusion. Allergic reaction symptoms may include hives or itching, skin redness, feeling dizzy or faint, shortness of breath, chest tightness or throat constriction, or facial swelling. Inform your doctor or nurse immediately if you notice any of these symptoms during or shortly after a ZALTRAP infusion.

• Wounds that heal slowly or incompletely: Uncommon(may affect up to 1 in 100 people) – this is when a wound has trouble healing or staying closed, or if a healed wound reopens. Your doctor will stop administering this medication at least 4 weeks before a planned surgery and until the wound has fully healed.

• An effect that affects your nervous system (also called "reversible posterior leukoencephalopathy syndrome" or RPLS):Uncommon(may affect up to 1 in 100 people) – symptoms may include headache, vision changes, feeling confused, or seizures, with or without high blood pressure.

Inform your doctor immediately if you experience any of the above side effects.

Other side effects include:

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

• Reduced white blood cell count (leucopenia)
• Reduced platelet count (thrombocytopenia)
• Loss of appetite
• Headache
• Nasal bleeding
• Change in voice, e.g. hoarse voice
• Difficulty breathing
• Painful mouth ulcers
• Stomach pain
• Hand and foot inflammation and numbness that occurs with chemotherapy (called "Erythema Palmo-Plantar Syndrome")
• Feeling tired or weak
• Weight loss
• Kidney problems, with increased creatinine (a marker of renal function)
• Liver problems, with increased liver enzymes.

Common(may affect up to 1 in 10 people)

• Urinary tract infection
• Upper respiratory tract inflammation and nasal congestion
• Mouth or throat pain
• Coughing
• Haemorrhoids, bleeding, or anal pain
• Oral inflammation
• Dental pain
• Skin color changes.

Uncommon(may affect up to 1 in 100 people)

• Increased protein in the urine, increased blood cholesterol, and fluid excess (edema) (also called "nephrotic syndrome")
• Clots in very small blood vessels (also called "microangiopathic thrombosis").

Not known(cannot be estimated from available data)

• Increased and weakened blood vessel walls or blood vessel wall tear (aneurysms and arterial dissections).

Reporting side effects:

If you experienceany type of side effect, consult your doctor, pharmacist, or nurse, even if it is apossibleside effect not listed in this leaflet.You can also report them directly through thenational reporting system included in theAppendix V. By reporting side effects, you can contribute to providing more information about the safety of this medicine.

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

Do not usethis medicationafter the expiration date that appears onthe boxafter CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C).

Store in the original packaging to protect it from light.

The information on the conservation and usage time of ZALTRAP, after it has been diluted and is ready to use, is described in the “Practical information for healthcare professionals on the preparation and handling of ZALTRAP 25 mg/ml concentrate for infusion solution”, at the end of this leaflet.

Do not use ZALTRAP if you observe particles or abnormal coloration of the medication in the vial or infusion bag.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacisthow to dispose of the containers andmedicines that you no longeruse. This will help protect the environment.

Composition of ZALTRAP

• The active ingredient is aflibercept. One milliliter of concentrate contains 25 mg of aflibercept. A vial with 4 ml of concentrate contains 100 mg of aflibercept. A vial with 8 ml of concentrate contains 200 mg of aflibercept.
• The other components are: sucrose, sodium chloride, sodium citrate dihydrate, citric acid monohydrate, polisorbate 20, sodium phosphate heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide and/or hydrochloric acid, and water for injection.

Appearance of the product and contents of the package

ZALTRAP is a concentrate for solution for infusion (sterile concentrate). The concentrate is a transparent, colorless to pale yellow solution.

• 4 ml of concentrate in a type I glass vial with a transparent borosilicate glass of 5 ml, sealed with a bridged cap with a flip-off capsule and a sealing disc. Each package contains 1 or 3 vials.
• 8 ml of concentrate in a type I glass vial with a transparent borosilicate glass of 10 ml, sealed with a bridged cap with a flip-off capsule and a sealing disc. Each package contains 1 vial.

Only some package sizes may be marketed.

Marketing Authorization Holder

Sanofi Winthrop Industrie

82 avenue Raspail

94250 Gentilly

France

Manufacturer

Sanofi-Aventis Deutschland GmbH

Industriepark Hoechst

65926 Frankfurt am Main

Germany

For more information about this medicine, contact the local representative of the Marketing Authorization Holder:

Last review date of this leaflet:

Other sources of information

The detailed information about this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu

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This information is intended solely for healthcare professionals:

INFORMATION FOR HEALTHCARE PROFESSIONALS ON THE PREPARATION AND HANDLING OF zaltrap 25mg/ml CONCENTRATE FOR SOLUTION FOR INFUSION

This information complements sections 3 and 5 for the user.

It is essential to read the entire content of this procedure before preparing the infusion solution.

ZALTRAP is a sterile, preservative-free, and apyrogenic concentrate, so the infusion solution must be prepared by a healthcare professional using safe handling and aseptic technique procedures.

When handling ZALTRAP, exercise caution, taking into account the use of containment equipment, personal protective equipment (e.g., gloves), and preparation procedures.

Preparation of the infusion solution

• Visually inspect the ZALTRAP vial before using it. The concentrate solution must be transparent and particle-free.
• According to the required dose for the patient, extract the necessary volume of ZALTRAP concentrate from the vial. It may be necessary to use more than one vial to prepare the infusion solution.

• Dilute it to the required administration volume with sodium chloride 9 mg/ml (0.9%) or glucose infusion solution at 5%. The final concentration of ZALTRAP for intravenous infusion must be maintained within the range of 0.6 mg/ml to 8 mg/ml of aflibercept.
• Use PVC bags with DEHP or polyolefin bags.
• The diluted solution must be inspected for the presence of particles and abnormal coloration before administration. If abnormal coloration or particles are observed, the reconstituted solution must be discarded.
• ZALTRAP is a single-use vial. Do not reuse the vial after the initial puncture. The unused concentrate solution must be discarded.

Valid period after dilution in the infusion bag

Chemical and physical stability has been demonstrated for use over 24 hours at 2-8°C, and for 8 hours at 25°C.

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

If not used immediately, the storage times in use and the conditions before use are the responsibility of the user and should not exceed, normally, 24 hours at 2-8°C, unless the dilution has been performed in controlled and validated aseptic conditions.

Administration form

ZALTRAP is administered only as an intravenous infusion, over 1 hour. Due to the hyperosmolarity of the ZALTRAP concentrate (1000 mOsmol/kg), the ZALTRAP concentrate should not be administered undiluted as an intravenous bolus. ZALTRAP should not be administered as an intravitreal injection (see section 2 of the leaflet).

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

The diluted ZALTRAP solutions must be administered using infusion sets that contain a 0.2-micron polyethersulfone filter.

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

• chlorinated polyvinyl chloride (PVC) containing bis(2-ethylhexyl) phthalate (DEHP)
• PVC without DEHP containing trioctyl trimellitate (TOTM)
• polypropylene
• polyethylene coated with PVC
• polyurethane

Do not use filters made of fluorinated polyvinylidene fluoride (PVDF) or nylon.

Disposal

The unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.