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 show it to your healthcare provider in the future.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience side effects, consult 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 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, consult your doctor, pharmacist, or nurse if there is any reason why you should not use these medicines.

Warnings and precautions

Consult 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 fatigue, 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 must maintain good oral hygiene (including regular brushing of your teeth) and have regular dental check-ups. If you wear dentures, make sure they fit properly. If you have previously received or are receiving treatment with intravenous 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 inflammation, or ulcers that do not heal or discharge, as these may be symptoms of osteonecrosis of the jaw.

• you suffer from 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 between your 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 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 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 the 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, difficulty speaking or swallowing. 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 (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 intravenously.

• you have ever had allergies - 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 intervention, or have a wound from an operation that has not yet healed. Your doctor will stop treatment temporarily 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 fluids (called "dehydration"). Your doctor will monitor you closely.

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

If you are in any of the above situations (or are not sure), inform 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 may include 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 men and women). This medicine may harm the unborn baby, as it stops 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 fertility in men and women. Consult your doctor for advice if you plan to have a child.

Contraception

Men and women who can have children must use an effective method of contraception:

• during treatment with ZALTRAP and
• for at least 6 months after the last dose of treatment.

Driving and using machines

You may experience side effects that affect your vision, concentration, or reaction. 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 administration. 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 normally 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 with other chemotherapy medicines, including "5-fluorouracil", "folinic acid", and "irinotecan". Your doctor will decide the appropriate 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 experience 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 stool color.

• Pain in the mouth, dental pieces, 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 loss of a tooth: 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) – 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) – can develop or worsen. If blood pressure is not controlled, it can cause stroke and heart and kidney problems. Your doctor should check your blood pressure during treatment.

• Heart failure(also known as heart failure); Uncommon(may affect up to 1 in 100 people) – Symptoms may include shortness of breath when lying down or when exerting yourself, 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, walking, coordination, or balance problems, or difficulty speaking or slurred speech.

• Blockage of the veins by a blood clot(also known as "venous thromboembolic events"): Common(may affect up to 1 in 10 people) – 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 of the affected leg, red or discolored skin of 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) – can cause serious infections. Your doctor will perform regular blood tests to check your white blood cell count throughout treatment. You may also be prescribed a medicine called "G-CSF" that helps prevent complications if your white blood cell count is too low. Infection symptoms may include fever, chills, cough, burning when urinating, or muscle pain. During treatment with this medicine, 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) – can occur a few minutes after infusion. Allergic reaction symptoms may include rash or itching, skin redness, feeling dizzy or faint, shortness of breath, chest tightness or throat, 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 medicine for at least 4 weeks before a planned 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 in the number of white blood cells (leukopenia)
• reduction in 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 (known as "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 known as "nephrotic syndrome")
• blood clots in very small blood vessels (also known as "thrombotic microangiopathy").

Unknown(cannot be estimated from 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 type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is 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 help provide more information on the safety of this medicine.

5. Storage of ZALTRAP

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

Do not use this medicine after the expiration date shown on the box after CAD. 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 to 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 notice particles or abnormal coloration of the medicine in the vial or infusion bag.

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

6. Package Contents and Additional Information

ZALTRAP Composition

• The active ingredient 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, monosodium phosphate monohydrate, sodium hydroxide and/or hydrochloric acid, and water for injectable preparations.

Product Appearance and Package Contents

ZALTRAP is a sterile 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 borosilicate glass vial, sealed with a flip-off cap and seal disc. Each package contains 1 or 3 vials.
• 8 ml of concentrate in a 10 ml type I borosilicate glass vial, sealed with a flip-off cap and seal disc. Each package contains 1 vial.

Only certain 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 on this medicine, contact the local representative of the Marketing Authorization Holder:

Date of the last revision of this leaflet: July 2019

Other sources of information

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

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 complements sections 3 and 5 for the user.

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

ZALTRAP is a sterile concentrate, without preservatives and apyrogenic, 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 needed for the patient, withdraw 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 solution at 9 mg/ml (0.9%) or glucose solution for infusion at 5%. The final concentration of ZALTRAP for intravenous infusion should be maintained in 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 eliminated.

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 are the responsibility of the user and should not normally exceed 24 hours at 2-8°C, unless the dilution has been performed under 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).

The diluted ZALTRAP solutions should be administered using infusion sets that contain 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)
• PVC without DEHP 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 medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.