ZALTRAP 25 mg/mL concentrate for infusion solution

Introduction

Package Leaflet: Information for the User

ZALTRAP 25 mg/ml Concentrate for Solution for Infusion

Aflibercept

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.Keep this leaflet, you may need to read it again, or give it to your healthcare provider in the future.

• Keep this leaflet, as you may need to read it again or give it to your healthcare provider in the future.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

1. What is ZALTRAP and what is it used for
2. What you need to know before you start using ZALTRAP
3. How to use ZALTRAP
4. Possible side effects
5. Storage of ZALTRAP
6. Contents of the pack and further information

1. What is ZALTRAP and what is it used for

What is ZALTRAP and how it works

ZALTRAP contains the active substance aflibercept, a protein that works 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.

What ZALTRAP is used for

ZALTRAP is a medicine used to treat advanced cancer of the colon or rectum (parts of the large intestine) in adults. It will be given to you together with other medicines called "chemotherapy", including "5-fluorouracil", "folinic acid", and "irinotecan".

2. What you need to know before you start using 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 eyes, as it could seriously damage them.

Also, read the package leaflets of the other medicines ("chemotherapy") that are part of your treatment, to check if they are suitable for you. If you are not sure, ask your doctor, pharmacist, or nurse if there is any reason why you should not use these medicines.

Warnings and precautions

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

• you have bleeding problems or if you experience any bleeding after treatment (see section 4), or if you notice extreme tiredness, weakness, dizziness, or a change in the color of your stools. 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 (pyorrhea), or a planned dental extraction, and especially if you have been treated before with bisphosphonates (used to treat or prevent bone problems). 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 starting treatment with ZALTRAP. While being treated with ZALTRAP, you should maintain good oral hygiene (including regular brushing of your teeth) and have regular dental check-ups. If you wear dentures, you should ensure they fit properly. If you have previously received or are receiving intravenous treatment with bisphosphonates, you should 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 with your mouth or teeth, such as tooth loss, pain, or swelling, or ulcers that do not heal or discharge, as these may be symptoms of osteonecrosis of the jaw.

• you have diseases where your intestine is inflamed, such as infection in a part of the intestinal wall (also called "diverticulitis"), stomach ulcers, or colitis. This is because ZALTRAP may increase the risk of developing holes in the intestinal wall. If this happens to you, your doctor will stop your treatment with ZALTRAP.

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

• you have high blood pressure. ZALTRAP may increase blood pressure (see section 4), and your doctor will need to check your blood pressure and may adjust the dose of your blood pressure medicines or the dose of ZALTRAP. Therefore, it is important that you tell 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 a blood vessel wall) or a tear in the wall of a blood vessel.

• you experience shortness of breath when you exert yourself or when you lie down, excessive tiredness, or swelling of your legs, which could be symptoms of heart failure.

• you experience signs of a blood clot (see section 4). The signs of a blood clot can vary, depending on where it occurs (e.g., lungs, legs, heart, or brain), but may include symptoms such as chest pain, cough, shortness of breath, or difficulty breathing. Other signs may include swelling of one or both legs, pain or tenderness in one or both legs, discoloration, and warmth of the skin of 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 a feeling of confusion, vision problems, walking, coordination, or balance problems, problems speaking, or difficulty speaking. If you experience any of these symptoms, tell your doctor immediately, as your doctor may want to treat your symptoms and stop treatment with ZALTRAP.

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

• your white blood cell count is too low. ZALTRAP may reduce the number of white blood cells in your blood, and your doctor will check your white blood cell count and may give you other medicines to increase it. If your white blood cell count is low, your doctor may need to delay your treatment.

• you have severe or persistent diarrhea, feel sick (nausea), or feel unwell (vomiting) – this can cause severe loss of body fluids (called "dehydration"). Your doctor may need to treat you with other medicines and/or give you fluids through a vein.

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

• you have had a tooth extracted or have had any type of surgery in the last 4 weeks, or are going to have an operation or medical or dental procedure, or have an unhealed wound from surgery. Your doctor will temporarily stop treatment before and after surgery.

• you experience seizures (fits). 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 fluids (called "dehydration"). Your doctor will monitor you closely.

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

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

During treatment, your doctor will perform various tests to check how your body is working and how the medicine is acting. The tests may include blood and urine tests, X-rays, or other imaging techniques and/or other tests.

ZALTRAP is given by infusion (drip) into one of your veins (intravenously) to treat advanced colon or rectal cancer. ZALTRAP must not be injected into your eyes, as it could seriously damage them.

Children and adolescents

This medicine is not for children or adolescents under 18 years, as the safety and benefits of using ZALTRAP in children and adolescents have not been established.

Using ZALTRAP with other medicines

Tell your doctor, pharmacist, or nurse if you are using, have recently used, or might use any other medicines. This includes medicines bought without a prescription or herbal medicines.

Pregnancy, breastfeeding, and fertility

Do not use ZALTRAP during pregnancy, unless your doctor decides that the benefit to you is greater than any possible risk to you or your baby.

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

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

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

Contraception

Women who can become pregnant must use an effective method of contraception:

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

Driving and using machines

You may experience side effects that affect your vision, concentration, or ability to react. If this happens, do not drive or use tools or machines.

ZALTRAP contains sodium

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

3. How to use ZALTRAP

ZALTRAP will be given to you by a doctor or nurse with experience in the use of "chemotherapy". It is given by infusion (drip) into one of your veins ("intravenously"). ZALTRAP must not be injected into your eyes, as it could seriously damage them.

The medicine must be diluted before it is given to you. Practical information on the handling and administration of ZALTRAP for doctors, nurses, and pharmacists when using this medicine is included in this package leaflet.

How much and how often you will receive treatment

• The infusion (drip) lasts about 1 hour.
• You will usually receive one infusion every 2 weeks.
• The recommended dose is 4 mg per kilogram of body weight. Your doctor will decide what dose is right for you.
• Your doctor will decide how often you will receive the medicine and if you need any change in the dose.

ZALTRAP will be given to you with other chemotherapy medicines, including "5-fluorouracil", "folinic acid", and "irinotecan". Your doctor will decide the right doses of these other chemotherapy medicines.

Treatment will continue until your doctor thinks it is beneficial for 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 Adverse Effects

Like all medicines, ZALTRAP can cause adverse effects, although not all people suffer from them. The adverse effects listed below were observed when ZALTRAP was administered along with chemotherapy:

Severe Adverse Effects

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

• Bleeding:Very Common(may affect more than 1 in 10 people) – includes nasal bleeding, but may also include severe bleeding in the intestine and other parts of the body that can be fatal. Symptoms include feeling very tired, weak and/or dizzy, or changes in the color of the stool.

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

• Holes in the intestine(also known as “gastrointestinal perforation”): Uncommon(may affect up to 1 in 100 people) – it is a hole in the stomach, esophagus, small intestine, or large intestine. It can be fatal. Symptoms include stomach pain, nausea (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 can form, for example, between the intestine and the skin. Sometimes, depending on where they occur, you may have an abnormal flow in that area. If you are unsure, consult your doctor.

• High blood pressure(also called “hypertension”): Very Common(may affect more than 1 in 10 people) – it can 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 known as cardiac insufficiency); Uncommon(may affect up to 1 in 100 people) – Symptoms may include shortness of breath when lying down or when exerting oneself, excessive tiredness, or swelling of the legs.

• Blockage of the arteries by a blood clot(also known as “arterial thromboembolic events”): Common(may affect up to 1 in 10 people) – this can lead to a stroke or heart attack. Symptoms may include pain or pressure in the chest, sudden feeling of numbness or weakness in the face, arms, or legs. Other symptoms include feeling confused, vision problems, difficulty walking, coordination or balance problems, or difficulty speaking or slurred speech.

• Blockage of the veins by a blood clot(also called “venous thromboembolic events”): Common(may affect up to 1 in 10 people) – it can include a clot in the lungs or legs. Symptoms may include chest pain, cough, shortness of breath, difficulty breathing, or coughing up blood. Other symptoms include swelling in one or both legs, pain or tenderness in one or both legs, at rest or when walking, warmth of the skin on the affected leg, red or discolored skin on 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 frequently observed in analyses. It can include swelling of the feet or entire body and may be related to kidney impairment.

• Low white blood cell count(also known as “neutropenia”): Very Common(may affect more than 1 in 10 people) – it can cause serious infections. Your doctor will perform regular blood tests to monitor your white blood cell count throughout treatment. They may also prescribe a medication called “G-CSF” that helps prevent complications if your white blood cell count is too low. Infection symptoms may include fever, chills, cough, burning sensation while urinating, or muscle pain. During treatment with this medication, you should take your temperature often.

• Diarrhea and dehydration:Very Common(may affect more than 1 in 10 people) for diarrhea and Common(may affect up to 1 in 10 people) for dehydration – severe diarrhea and nausea (vomiting) can cause excessive loss of fluid (known as “dehydration”) and salts from the 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 nausea (vomiting).

• Allergic reactions: Common(may affect up to 1 in 10 people) – they can occur a few minutes after infusion. Allergic reaction symptoms may include rash or itching, redness of the skin, feeling dizzy or faint, shortness of breath, chest tightness or throat constriction, or swelling of the face. 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 for at least 4 weeks before scheduled surgery and until the wound heals completely.

• An adverse effect that affects your nervous system(known as “posterior reversible encephalopathy syndrome” or PRES): Uncommon(may affect up to 1 in 100 people) – symptoms may include headache, changes in vision, feeling confused or seizures, with or without high blood pressure.

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

Other adverse effects include:

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

• reduction of white blood cell count (leucopenia)
• reduction of the number of certain blood cells that help it clot (thrombocytopenia)
• decreased appetite
• headache
• nasal bleeding
• change in voice, e.g., hoarse voice
• difficulty breathing
• painful ulcers in the mouth
• stomach pain
• inflammation and numbness of the hands and feet that occurs with chemotherapy (called “Palmar-Plantar Erythrodysesthesia Syndrome”)
• feeling tired or weak
• weight loss
• kidney problems, with an increase in creatinine (a marker of kidney function)
• liver problems, with an increase in liver enzymes.

Common(may affect up to 1 in 10 people)

• urinary tract infection
• inflammation inside the nose and upper throat
• mouth or throat pain
• runny nose
• hemorrhoids, bleeding, or pain in the anus
• inflammation inside the mouth
• toothache
• skin color changes.

Uncommon(may affect up to 1 in 100 people)

• an increase in protein in the urine, an increase in blood cholesterol, and inflammation due to excess fluid (edema) (also called “nephrotic syndrome”)
• blood clots in very small blood vessels (also called “microangiopathic thrombosis”).

Not known(cannot be estimated from the available data)

• increase and weakening of the wall of a blood vessel or tear of the blood vessel wall (aneurysms and arterial dissections).

Reporting of adverse effects:

If you experience any kind of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

5. Storage of ZALTRAP

Keep this medication out of sight and reach of children.

Do not use this medication after the expiration date stated on the carton after EXP. The expiration date is the last day of the month indicated.

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

Store in the original packaging to protect it from light.

Information on the storage and use of ZALTRAP, after it has been diluted and is ready for use, is described in the “Practical information for healthcare professionals on the 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 observe particles or abnormal coloration of the medication in the vial or infusion bag.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medications that are no longer needed. This will help protect the environment.

6. Container Contents and Additional Information

ZALTRAP Composition

• The active substance is aflibercept. One ml 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, polysorbate 20, disodium phosphate heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide and/or hydrochloric acid, and water for injectable preparations.

Product Appearance and Container Contents

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

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

Only some 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 more information about this medicinal product, contact the local representative of the Marketing Authorisation Holder:

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu

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This information is intended only for healthcare professionals:

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

This information supplements sections 3 and 5 for the user.

It is important to read the entire contents 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 procedures and aseptic technique.

Caution should be exercised when handling ZALTRAP, 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 use. The concentrated solution must be clear and particle-free.
• According to the dose required for the patient, withdraw the necessary volume of ZALTRAP concentrate from the vial. More than one vial may be necessary to prepare the infusion solution.

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

Validity period after dilution in the infusion bag

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

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

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

Method of administration

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 for single use (single dose).

Diluted ZALTRAP solutions should be administered using infusion sets containing a 0.2 microns polyethersulfone filter.

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-coated PVC
• polyurethane

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

Disposal

Disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.