Zaltrap 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

ZALTRAP 25 mg/ml concentrate for solution for infusion

Aflibercept

Read the entire 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 provide it to healthcare professionals in the future.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What ZALTRAP is and what it is used for

What ZALTRAP is and how it works

ZALTRAP contains the active substance aflibercept, a protein that works by blocking the growth of new blood vessels within the tumor. Tumors require nutrients and oxygen from the blood in order to grow. By inhibiting the formation of new blood vessels, ZALTRAP helps to stop or slow tumor growth.

What ZALTRAP is used for

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

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

Do not use ZALTRAP

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

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

Warnings and precautions

Talk to 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 color 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 (periodontitis), or a planned dental extraction, especially if you have previously been treated with bisphosphonates (used to treat or prevent bone problems). An adverse effect called osteonecrosis (damage to the jawbone) has been reported in cancer patients treated with ZALTRAP. You may be advised to have a dental examination before starting treatment with ZALTRAP. While being treated with ZALTRAP, you should maintain good oral hygiene (including regular tooth brushing) and have periodic dental check-ups. If you wear dentures, ensure they are properly fitted. Dental procedures or dental surgery (e.g., tooth extraction) should be avoided if you have previously or are currently receiving intravenous bisphosphonate treatment. Inform your doctor about your dental treatments and inform 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 non-healing sores or discharge, as these may be symptoms of mandibular osteonecrosis.

• you suffer from intestinal disorders involving inflammation of the intestine, such as infection in part of the intestinal wall (also known as “diverticulitis”), stomach ulcers, or colitis. This is because ZALTRAP may increase the risk of developing intestinal wall perforations. If this occurs, your doctor will stop your treatment with ZALTRAP.

• you have had abnormal tube-like connections or channels within your body between internal organs and the skin or other tissues (also called “fistulas”). If you develop such connections or channels 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 monitor your blood pressure and may adjust the dose of your blood pressure medications or your dose of ZALTRAP. Therefore, it is important to inform your doctor, pharmacist, or nurse if you have any other heart problems, as blood pressure could worsen.

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

• you experience shortness of breath (dyspnea) when exerting yourself or when lying down, excessive fatigue, or swelling in your legs, which could 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, cough, shortness of breath, or difficulty breathing. Other signs may include swelling in one or both legs, pain or tenderness in one or both legs, skin discoloration and warmth in the affected leg, or visible veins. It may also present as a sudden sensation of numbness or weakness in the face, arms, or legs. Other symptoms include confusion, vision problems, difficulty walking, lack of coordination or balance, trouble pronouncing words, or difficulty speaking. If you experience any of these symptoms, inform your doctor immediately, as your doctor may need 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 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 monitor your white blood cell count and may administer other medicines to increase them. If your white blood cell count is low, your doctor may need to delay your treatment.

• you have severe or persistent diarrhea, feel unwell (nausea), or are unwell (vomiting)—this may lead to severe loss of body fluids (called “dehydration”). Your doctor may need to treat you with other medicines and/or administer fluids intravenously.

• you have ever had allergies—as serious allergic reactions may occur during treatment with ZALTRAP (see section 4). Your doctor may need to treat the allergic reaction or stop treatment with ZALTRAP.

• you have had a tooth removed or undergone any type of surgery within the last 4 weeks, or are scheduled for a medical, surgical, or dental procedure, or have a surgical wound that has not yet healed. Your doctor will temporarily stop treatment before and after surgery.

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

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

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

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

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

ZALTRAP is administered by intravenous infusion (drip) into one of your veins to treat advanced colon or rectal cancer. ZALTRAP must not be injected into the eyes, as it may severely damage them.

Children and adolescents

This medicine is not intended for use in children or adolescents under 18 years of age, as the safety and benefit of ZALTRAP have not been established in children and adolescents.

Use of ZALTRAP with other medicines

Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might need to take any other medicines. This may include medicines purchased without a prescription or herbal remedies.

Pregnancy, breastfeeding, and fertility

You must not use ZALTRAP during pregnancy unless your doctor decides that the benefit to you outweighs any possible risk to you or your baby.

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

If you are breastfeeding, consult your doctor before receiving 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

Women who are able to have children 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 reaction ability. If this occurs, do not drive or operate tools or machinery.

ZALTRAP contains sodium

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

3. How to use ZALTRAP

ZALTRAP will be administered to you by a doctor or nurse experienced in the use of chemotherapy. It is given as an intravenous infusion (drip) into one of your veins. ZALTRAP must not be injected into the eyes, as it could cause severe damage.

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

How much and how often you will receive treatment

• The infusion lasts approximately 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 determine the correct dose for you.
• Your doctor will decide how often you will receive the medicine and whether any dose adjustments are needed.

ZALTRAP will be given together with other chemotherapy medicines, including 5-fluorouracil, folinic acid, and irinotecan. Your doctor will determine the appropriate doses of these other chemotherapy medicines.

Treatment will continue as long as your doctor considers it beneficial for you and the side effects remain acceptable.

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

4. Possible adverse effects

Like all medicines, ZALTRAP may cause adverse effects, although not everyone experiences them. The adverse effects listed below were observed when ZALTRAP was administered in combination with chemotherapy:

Serious adverse effects

Tell your doctor immediately if you experience any of the following serious adverse effects – you may require urgent medical treatment:

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

• Pain in the mouth, teeth, and/or jaw, swelling or sores 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) – a hole in the stomach, esophagus, small intestine, or large intestine. This can be fatal. 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 tube-like or channel connections may form, for example, between the intestine and the skin. Sometimes, depending on where they occur, you may experience abnormal discharge at the site. If you are unsure, consult your doctor.

• High blood pressure (also called "hypertension"): Very common (may affect more than 1 in 10 people) – may develop or worsen. If blood pressure is not controlled, it may lead to stroke and heart or kidney problems. Your doctor must monitor your blood pressure during treatment.

• Heart failure (also called cardiac failure): Uncommon (may affect up to 1 in 100 people) – Symptoms may include shortness of breath when lying down or exerting yourself, excessive fatigue, or swelling in the legs.

• Blockage of arteries by a blood clot (also called "arterial thromboembolic events"): Common (may affect up to 1 in 10 people) – this may lead to stroke or heart attack. Symptoms may include chest pain or pressure, sudden numbness or weakness in the face, arms, or legs. Other symptoms include confusion, vision problems, walking difficulties, coordination or balance problems, or difficulty speaking or trouble forming words.

• Blockage of veins by a blood clot (also called "venous thromboembolic events"): Common (may affect up to 1 in 10 people) – may 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 in the skin of 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 frequently observed in laboratory tests. It may include swelling of the feet or entire body and may be related to kidney problems.

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

• 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) may cause you to lose large amounts of fluid (called "dehydration") and salts (electrolytes) from your body. Symptoms may include dizziness, especially when standing up. You may require hospital treatment. Your doctor will give you medicines to stop or treat diarrhea and nausea (vomiting).

• Allergic reactions: Common (may affect up to 1 in 10 people) – may occur a few minutes after the infusion. Symptoms of allergic reaction may include rash or itching, skin redness, feeling dizzy or faint, shortness of breath, tightness in the chest or throat, 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 occurs when a wound has difficulty healing or staying closed, or when a healed wound reopens. Your doctor will stop administering this medicine for at least 4 weeks before any planned surgery and until the wound has completely healed.

• An adverse effect affecting your nervous system (called "posterior reversible encephalopathy syndrome" or PRES): Uncommon (may affect up to 1 in 100 people) – symptoms may include headache, changes in vision, confusion, or seizures, with or without high blood pressure.

Tell 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)

• decrease in the number of white blood cells (leukopenia)
• decrease in certain blood cells that help your blood to clot (thrombocytopenia)
• decreased appetite
• headache
• nosebleeds
• change in voice, e.g., hoarseness
• difficulty breathing
• painful mouth ulcers
• stomach pain
• swelling 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
• changes in skin color.

Uncommon (may affect up to 1 in 100 people)

• increase in protein in the urine, increase in blood cholesterol, and fluid retention causing swelling (edema) (also called "nephrotic syndrome")
• blood clots in very small blood vessels (also called "thrombotic microangiopathy").

Not known (cannot be estimated from the available data)

• enlargement and weakening of a blood vessel wall or tearing of a blood vessel wall (aneurysms and arterial dissections).

Reporting of adverse effects:

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You may 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 expiry date stated on the carton after EXP. The expiry date refers to the last day of the month indicated.

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

Keep in the original packaging to protect from light.

Information on the storage and duration of use of ZALTRAP after dilution and once ready for administration 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 particles or abnormal discoloration of the medicine are observed in the vial or infusion bag.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer use. This will help protect the environment.

6. Contents of the pack and other information

Composition of ZALTRAP

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

Appearance of the product 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 concentrate in a 5 ml clear type I glass vial, closed with a flip-off cap and sealed with a seal disc. Each pack contains 1 or 3 vials.
• 8 ml concentrate in a 10 ml clear type I glass vial, closed with a flip-off cap and sealed with a 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, please contact the local representative of the Marketing Authorisation Holder:

Date of the most recent review of this leaflet:

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 for healthcare professionals only:

PRACTICAL 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 important to read all the contents of this procedure before preparing the infusion solution.

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

Extreme caution must 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 concentrate solution should be clear and free from particles.

• Depending on the required dose for the patient, withdraw the necessary volume of ZALTRAP concentrate from the vial. More than one vial may be needed to prepare the infusion solution.

• Dilute to the required administration volume with either 9 mg/ml (0.9%) sodium chloride solution or 5% glucose solution for infusion. 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.

• Infusion bags made of PVC with DEHP or polyolefin infusion bags should be used.

• The diluted solution should 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 initial puncture. Any unused concentrate solution must be discarded.

Validity period after dilution in the infusion bag

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

From a microbiological standpoint, the infusion solution should be used immediately.

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

Method of administration

ZALTRAP is administered only as a 1-hour intravenous infusion. Due to the high osmolarity of the ZALTRAP concentrate (1000 mOsmol/kg), undiluted ZALTRAP concentrate must not be administered as an intravenous bolus. ZALTRAP must not be administered as an intravitreal injection (see section 2 of the summary of product characteristics).

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

Diluted ZALTRAP solutions must be administered using infusion sets containing a 0.2-micron polyethersulfone filter.

Infusion sets must be manufactured from one of the following materials:

• Polyvinyl chloride (PVC) containing bis(2-ethylhexyl) phthalate (DEHP)
• DEHP-free PVC containing trioctyl trimellitate (TOTM)
• Polypropylene
• PVC-coated polyethylene
• Polyurethane

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

Disposal

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