VEGZELMA 25 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

VEGZELMA 25 mg/ml concentrate for solution for infusion

bevacizumab

This medicinal product is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. The last section of the leaflet includes information on how to report side effects.

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.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What is VEGZELMA and what is it used for

The active substance of VEGZELMA is bevacizumab, a humanized monoclonal antibody (a type of protein that is normally produced by the immune system to help the body defend itself against infections and cancer). Bevacizumab selectively binds to a protein called vascular endothelial growth factor (VEGF), which is located on the walls of blood and lymphatic vessels in the body. The VEGF protein causes blood vessels to grow into the tumor, supplying it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels that provide the necessary nutrients and oxygen for the tumor.

VEGZELMA is a medicine used to treat adult patients with advanced colon or rectal cancer. VEGZELMA will be given in combination with a chemotherapy treatment that contains a fluoropyrimidine medicine.

VEGZELMA is also used to treat adult patients with metastatic breast cancer. When used in patients with breast cancer, it will be given with a chemotherapy medicine called paclitaxel or capecitabine.

VEGZELMA is also used to treat adult patients with advanced non-small cell lung cancer. VEGZELMA will be given along with a platinum-based chemotherapy regimen.

VEGZELMA is also used to treat adult patients with advanced non-small cell lung cancer when the cancer cells have specific mutations in a protein called epidermal growth factor receptor (EGFR). VEGZELMA will be given in combination with erlotinib.

VEGZELMA is also used to treat adult patients with advanced kidney cancer. When used in patients with kidney cancer, it will be given with another type of medicine called interferon.

VEGZELMA is also used to treat adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. When used in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, it will be given in combination with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease at least 6 months after they were last treated with a platinum-based chemotherapy regimen, VEGZELMA will be given in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease at least 6 months after they were last treated with a platinum-based chemotherapy regimen, VEGZELMA will be given in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

VEGZELMA is also used to treat adult patients with persistent, recurrent, or metastatic cervical cancer. VEGZELMA will be given in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum-based therapy.

2. What you need to know before you are given VEGZELMA

Do not use VEGZELMA

• if you are allergic (hypersensitive) to bevacizumab or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic (hypersensitive) to products derived from Chinese Hamster Ovary (CHO) cells or other recombinant human or humanized antibodies.
• if you are pregnant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using VEGZELMA

• VEGZELMA may increase the risk of perforation of the intestine wall. If you have any disease that causes inflammation in the abdomen (e.g., diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.

• VEGZELMA may increase the risk of developing an abnormal connection between two organs or vessels. The risk of developing a connection between the vagina and any part of the intestine may increase if you have persistent, recurrent, or metastatic cervical cancer.

• This medicine may increase the risk of bleeding or problems with wound healing after surgery. If you are going to have surgery, have had major surgery in the last 28 days, or have an unhealed surgical wound, you should not use this medicine.

• VEGZELMA may increase the risk of developing serious skin or deep skin layer infections, especially if you have had perforation of the intestine wall or problems with wound healing.

• VEGZELMA may increase the risk of high blood pressure. If you have uncontrolled high blood pressure, consult your doctor to ensure that your blood pressure is under control before starting treatment with VEGZELMA.

• If 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.

• This medicine may increase the risk of having protein in the urine, especially if you already have high blood pressure.

• The risk of developing blood clots or blockages in your arteries (a type of blood vessel) may increase if you are over 65 years old, if you have diabetes, or if you have had blood clots or blockages in your arteries in the past. Consult your doctor, as blood clots or blockages can cause a heart attack and stroke.

• VEGZELMA may also increase the risk of developing blood clots or blockages in your veins (a type of blood vessel).

• This medicine may cause bleeding, especially bleeding related to the tumor. Consult your doctor if you have a history of or are at risk of bleeding disorders (bleeding) or are taking medicines that thin your blood for any reason.

• VEGZELMA may cause bleeding in and around your brain. Consult your doctor if you have metastatic cancer that affects your brain.

• VEGZELMA may increase the risk of bleeding in your lungs, including coughing up blood. Consult your doctor if you have noticed this before.

• VEGZELMA may increase the risk of your heart becoming weak. It is important that you inform your doctor if you have ever been treated with anthracyclines (a specific type of chemotherapy used to treat certain types of cancer, such as doxorubicin) or have received radiation therapy to the chest, or if you have heart disease.

• This medicine may cause infections and decrease the number of neutrophils (a type of blood cell important for protecting you against bacteria).

• VEGZELMA may cause hypersensitivity (including anaphylactic reactions) and/or infusion-related reactions (reactions related to the injection of the medicine). Consult your doctor, pharmacist, or nurse if you have experienced problems after injections, such as dizziness/fainting, difficulty breathing, swelling, or skin rash.

• A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with treatment with VEGZELMA. If you have a headache, changes in vision, confusion, or seizures with or without high blood pressure, consult your doctor.

Please consult your doctor even if any of the above situations apply to you or have occurred in the past.

Before starting treatment with VEGZELMA or during treatment with VEGZELMA:

Before you start treatment with VEGZELMA, you may be advised to have a dental check-up.

Children and adolescents

VEGZELMA is not recommended for use in children and adolescents under 18 years of age, as the safety and efficacy in these patients have not been established.

There have been reports of bone tissue death (osteonecrosis) in bones other than the jaw in patients under 18 years of age treated with bevacizumab.

Other medicines and VEGZELMA

Tell your doctor, pharmacist, or nurse if you are using, have recently used, or might use any other medicines.

The combination of VEGZELMA with another medicine called sunitinib malate (prescribed for kidney or gastrointestinal cancer) may cause serious side effects. Consult your doctor to ensure that you do not combine these medicines.

Consult your doctor if you are receiving platinum-based or taxane-based therapy for metastatic breast or lung cancer. These therapies in combination with VEGZELMA may increase the risk of serious side effects.

Tell your doctor if you have recently received or are receiving radiation therapy.

Pregnancy, breastfeeding, and fertility

Do not use VEGZELMA if you are pregnant. VEGZELMA may harm your unborn baby, as it may prevent the formation of new blood vessels. Your doctor should advise you on the use of contraceptive methods during treatment with VEGZELMA and for at least 6 months after the last dose of VEGZELMA.

Inform your doctor immediately if you are already pregnant, become pregnant during treatment with VEGZELMA, or plan to become pregnant in the near future.

Do not breastfeed your baby during treatment with VEGZELMA and for at least 6 months after the last dose of VEGZELMA, as this medicine may interfere with the growth and development of your baby.

VEGZELMA may affect female fertility. Consult your doctor for more information. Consult your doctor, pharmacist, or nurse before using any medicine.

Driving and using machines

VEGZELMA has not been shown to reduce your ability to drive or use tools or machines. However, somnolence and fainting have been reported with the use of VEGZELMA. If you experience symptoms that affect your vision or concentration, or your reaction time, do not drive or use machines until the symptoms disappear.

VEGZELMA contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per vial, which is essentially "sodium-free".

3. How to use VEGZELMA

Dose and frequency of administration

The dose of VEGZELMA you need depends on your weight and the type of cancer being treated. The recommended dose is 5 mg, 7.5 mg, 10 mg, or 15 mg per kilogram of body weight. Your doctor will prescribe the most suitable dose of VEGZELMA for you, and you will be treated with VEGZELMA once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to treatment and should continue until VEGZELMA can no longer slow down tumor growth. Your doctor will discuss these aspects with you.

Form and route of administration

VEGZELMA is a concentrate for solution for infusion. Depending on the dose prescribed for you, a fraction or all of the contents of the VEGZELMA vial will be diluted with sodium chloride solution before administration. A doctor or nurse will give you this diluted VEGZELMA solution as an intravenous infusion (by drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion can be given over 60 minutes. Subsequent infusions can be given over 30 minutes.

Administration of VEGZELMA must be temporarily interrupted:

Administration of VEGZELMA must be permanently stopped if you have:

If you use more VEGZELMA than you should

If you forget to use VEGZELMA

If you stop treatment with VEGZELMA

Stopping treatment with VEGZELMA may reduce its effect on tumor growth. Do not stop treatment with VEGZELMA unless you have discussed it with your doctor.

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, this medicine can cause adverse effects, although not all people suffer from them.

If you experience adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects that do not appear in this prospectus.

The adverse effects mentioned below have been observed when VEGZELMA is administered with chemotherapy. This does not necessarily mean that these adverse effects were strictly caused by VEGZELMA.

Allergic Reactions

If you have an allergic reaction, consult your doctor or healthcare professional immediately. The signs may include: difficulty breathing or chest pain. You may also experience redness or flushing of the skin or rash, chills and tremors, feeling of dizziness (nausea) or feeling of discomfort (vomiting), swelling, dizziness, rapid heartbeat, loss of consciousness.

You should seek help immediately if you suffer from any of the adverse effects mentioned below.

Severe adverse effects that may be veryfrequent(may affect more than 1 in 10 patients) include:

• high blood pressure,
• feeling of numbness or tingling in hands or feet,
• decrease in the number of blood cells, including white blood cells that help fight infections (this may be accompanied by fever), and platelets that help blood clot,
• feeling of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Severe adverse effects that may be frequent(may affect up to 1 in 10 patients) include:

• perforation of the intestine,
• bleeding, including hemorrhage in the lungs in patients with non-small cell lung cancer,
• blockage of the arteries by embolism,
• blockage of the veins by embolism,
• blockage of the blood vessels of the lungs by embolism,
• blockage of the veins of the legs by embolism,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, sensitivity, pain, or blisters on the fingers or toes,
• decrease in the number of red blood cells,
• lack of energy,
• alterations in the stomach and intestine,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced urine output or dark urine,
• inflammation of the mucous membrane lining of the mouth and intestine, lungs and airways, reproductive system and urinary tract,
• sores in the mouth and the tube that goes from the mouth to the stomach, which can be painful and cause difficulty swallowing,
• pain, including headache, back pain, in the pelvis and anal regions,
• localized pockets of pus,
• infection, and in particular infection in the blood or bladder,
• decrease in blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (protein in the urine),
• difficulty breathing or decrease in oxygen levels in the blood,
• infections of the skin or deeper layers under the skin,
• fistula: abnormal tube-like communication between internal organs and the skin or other tissues that are not normally connected, including communications between the vagina and intestine in patients with cervical cancer,
• allergic reactions (the signs may include difficulty breathing, redness of the face, skin rash, low or high blood pressure, low oxygen levels in the blood, chest pain or nausea/vomiting).

Severe adverse effects that may be rare(may affect up to 1 in 1000 patients) include:

sudden and severe allergic reaction with difficulty breathing, swelling, dizziness, rapid heartbeat, sweating, and loss of consciousness (anaphylactic shock).

Severe adverse effects with unknownfrequency (cannot be estimated from the available data) include:

• severe infections of the skin or deeper layers under the skin, especially if you had perforations in the intestinal wall or problems with wound healing,
• negative effect on the woman's ability to have children (see below for more recommendations),
• brain disease with symptoms such as seizures (attacks), headache, confusion, and changes in vision (Posterior Reversible Encephalopathy Syndrome or PRES),
• symptoms suggesting changes in the normal function of the brain (headaches, changes in vision, confusion, or seizures), and high blood pressure,
• increase and weakening of the wall of a blood vessel or tear of the wall of a blood vessel (aneurysms and arterial dissections).
• obstruction of small blood vessels in the kidney,
• abnormally high blood pressure in the blood vessels of the lungs that makes the right side of the heart work harder than normal,
• perforation in the wall of the cartilage that separates the nasal openings,
• perforation in the stomach or intestine,
• ulcer or perforation in the lining of the stomach or small intestine (these signs may include abdominal pain, feeling of bloating, black stools, stools with blood, or blood in the vomit),
• bleeding from the lower part of the large intestine,
• lesions in the gums, with the jawbone exposed that do not heal and may be associated with pain and inflammation of the surrounding tissues (for more recommendations, see the list of adverse effects below),
• perforation of the gallbladder (the symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you notice any of these adverse effects mentioned, seek medical attention as soon as possible.

Non-severe adverse effects that are very frequent(may affect more than 1 in 10 patients) are:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech disorders,
• taste disorders,
• nasal discharge,
• dry skin, peeling, and inflammation of the skin, changes in skin color,
• weight loss,
• nosebleeds.

Non-severe adverse effects that are frequent(may affect up to 1 in 10 patients) are:

• changes in voice and hoarseness.

Patient over 65 years of age have a higher risk of experiencing the following:

• embolism in the arteries that can cause stroke or heart attack,
• reduction in the number of white blood cells and platelets (that help with blood clotting) in the blood,
• diarrhea,
• discomfort,
• headache,
• fatigue,
• high blood pressure.

VEGZELMA may also cause changes in laboratory tests that your doctor performs. These changes may include a decrease in the number of white blood cells in the blood, in particular neutrophils (a type of white blood cell that helps fight infections), presence of protein in the urine, decrease in potassium, sodium, or phosphorus in the blood, increase in blood sugar, increase in alkaline phosphatase (an enzyme) in the blood, decrease in hemoglobin (which is found in red blood cells and carries oxygen), which can be severe.

Pain in the mouth, teeth, and/or jaw, swelling or sores in the mouth, numbness or feeling of heaviness of the jaw, or loss of a tooth. These may be signs and symptoms of bone damage in the jaw (osteonecrosis). Inform your doctor and dentist immediately if you experience any of them.

Pre-menopausal women (women who have a menstrual cycle) may notice that their periods become irregular or disappear and may experience fertility problems. If you are thinking of having children, you should consult your doctor before starting treatment.

VEGZELMA has been developed and manufactured to treat cancer by injection into the bloodstream. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for use in this way. When bevacizumab is injected directly into the eye (unapproved use), the following side effects may occur:

• Infection or inflammation of the eyeball,
• Redness of the eye, small particles or spots in the vision (floaters), eye pain,
• Flashes of light with floaters, with progression to partial loss of vision,
• Increased eye pressure,
• Bleeding in the eye.

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 does not appear in this prospectus. 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 medicine.

5. Storage of VEGZELMA

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

Do not use this medicine after the expiration date that appears on the packaging and on the label of the vial after CAD. The expiration date is the last day of the month indicated.

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

Do not freeze.

Keep the vial in the outer packaging to protect it from light.

The solution for infusion should be administered immediately after dilution. If it is not administered immediately, the storage times and conditions are the responsibility of the user and would normally not be more than 24 hours at between 2 °C and 8 °C, unless the infusion solutions have been prepared in a sterile environment. When the dilution has been prepared in a sterile environment, VEGZELMA remains stable for 60 days at between 2 °C and 8 °C plus 7 additional days at between 2 °C and 30 °C.

Do not use VEGZELMA if you observe foreign particles or discoloration before administration.

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

6. Package Contents and Additional Information

Composition of VEGZELMA

The active ingredient is bevacizumab.

• Each ml of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 or 16.5 mg/ml when diluted as recommended.

Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.

Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.

• The other ingredients are trehalose dihydrate, sodium phosphate, polysorbate 20, and water for injectable preparations.

Appearance of the Product and Package Contents

VEGZELMA is a concentrate for solution for infusion. The concentrate is a clear, colorless to pale brown liquid contained in a glass vial with a rubber stopper. Each vial contains either 100 mg of bevacizumab in 4 ml of solution or 400 mg of bevacizumab in 16 ml of solution. Each package of VEGZELMA contains 1 vial or 10 vials.

Marketing Authorization Holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B tower

Hungary

Manufacturer

Millmount Healthcare Ltd.

Block 7

City North Business Campus

Stamullen, Co. Meath K32 YD60

Ireland

Nuvisan GmbH

Wegenerstraße 13

89231 Neu Ulm

Germany

Nuvisan France SARL

2400, Route des Colles

06410, Sophia Antipolis

France

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of the Last Revision of this Prospectus <{MM/AAAA}>

Other Sources of Information

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