Patient Information Leaflet

VEGZELMA 25 mg/ml Concentrate for Solution for Infusion

bevacizumab

This medicine is subject to additional monitoring, which will speed up the detection of any new information about its safety. You can contribute by reporting any side effects you may experience. The final part of section 4 includes information on how to report these side effects.

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

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult 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.

The active ingredient 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, English acronym), which is located in the walls of blood and lymphatic vessels of the body. The VEGF protein causes blood vessels to grow within the tumor, which supplies it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels, which provide the necessary nutrients and oxygen for the tumor.

VEGZELMA is a medication used for the treatment of adult patients with advanced colorectal or rectal cancer. VEGZELMA will be administered in combination with a chemotherapy regimen containing a fluoropyrimidine medication.

VEGZELMA is also used for the treatment of adult patients with metastatic breast cancer. When used in patients with breast cancer, it will be administered with a chemotherapy medication called paclitaxel or capecitabine.

VEGZELMA is also used for the treatment of adult patients with advanced non-small cell lung cancer. VEGZELMA will be administered along with a platinum-based chemotherapy regimen.

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

VEGZELMA is also used for the treatment of adult patients with advanced renal cancer. When used in patients with renal cancer, it will be administered with another type of medication called interferon.

VEGZELMA is also used for the treatment of 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 administered 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 of at least 6 months since their last treatment with a platinum-based chemotherapy regimen, VEGZELMA will be administered 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 of at least 6 months since their last treatment with a platinum-based chemotherapy regimen, VEGZELMA will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

VEGZELMA is also used for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer. VEGZELMA will be administered in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum-based therapy.

No use VEGZELMA

• If you are allergic (hypersensitive) to bevacizumab or any of the other components of this medication (listed in section 6).
• If you are allergic (hypersensitive) to Chinese hamster ovary (CHO) cell-derived products or to other recombinant human or humanized antibodies.
• If you are pregnant.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use VEGZELMA.

• VEGZELMA may increase the risk of causing intestinal wall perforations. If you have any abdominal inflammation-related disease (e.g. diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.

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

• This medication may increase the risk of bleeding or problems with surgical wound healing. If you are to undergo surgery, have undergone major surgery in the last 28 days, or have an unhealed surgical wound, do not use this medication.

• VEGZELMA may increase the risk of developing severe skin or deep tissue infections, especially if you have had intestinal wall perforations or wound healing problems.

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

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

• This medication increases the risk of having protein in the urine, especially if you already have high blood pressure.

• The risk of developing arterial thrombi or emboli may increase if you are over 65 years old, have diabetes, or have had arterial thrombi or emboli in the past. Consult your doctor, as thrombi or emboli can cause heart attacks and strokes.

• VEGZELMA may also increase the risk of developing venous thrombi or emboli.

• This medication may cause bleeding, especially tumor-related bleeding. Consult your doctor if you have a tendency or family history of coagulation disorders (bleeding) or are taking blood-thinning medications 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 pulmonary bleeding, including coughing or expectoration of blood. Consult your doctor if you have previously noticed this.

• VEGZELMA may increase the risk of heart failure. It is essential to 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 chest radiation, or if you have a heart disease.

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

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

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

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

Before starting treatment with VEGZELMA or during VEGZELMA treatment:

• If you have or have had mouth pain, tooth pain, or gum pain, swelling, or ulcers, or tooth loss, inform your doctor and dentist immediately.
• If you need to undergo invasive dental treatment or surgery, inform your dentist that you are being treated with VEGZELMA, especially when also receiving or having received bisphosphonates in your blood.

You may be advised to have a dental check-up before starting VEGZELMA treatment.

Children and adolescents

VEGZELMA is not recommended for children and adolescents under 18 years old, as its safety and efficacy have not been established in these patients.

Cases of osteonecrosis (death of bone tissue) in bones other than the jaw have been reported in patients under 18 years old treated with bevacizumab.

Other medications and VEGZELMA

Inform your doctor, pharmacist, or nurse if you are using, have used recently, or may need to use any other medication.

The combination of VEGZELMA with another medication called sunitinib malate (prescribed for renal and gastrointestinal cancer) may cause severe side effects. Consult your doctor to ensure that you are not combining these medications.

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

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

Pregnancy, breastfeeding, and fertility

You should not use VEGZELMA if you are pregnant. VEGZELMA may harm the fetus, as it may inhibit the formation of new blood vessels. Your doctor should advise you on the use of contraceptive methods during VEGZELMA treatment and at least 6 months after the last dose of VEGZELMA.

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

You should not breastfeed your baby during VEGZELMA treatment and at least 6 months after the last dose of VEGZELMA, as this medication may interfere with your baby's growth and development.

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

Driving and operating machinery

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

VEGZELMA contains sodium

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

Dose and administration frequency

The dose of VEGZELMA required depends on your weight and the type of cancer to be 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 your case, 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 you should continue it 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, a fraction or the entire contents of the VEGZELMA vial will be diluted with sodium chloride solution before administration. A doctor or nurse will administer this diluted VEGZELMA solution as an intravenous infusion (by drip in your veins). The first infusion will be administered over 90 minutes. If you tolerate this infusion well, the second can be administered over 60 minutes. Subsequent infusions can be administered over 30 minutes.

VEGZELMA administration must be temporarily interrupted:

• if you develop severe hypertension that requires treatment with antihypertensive medications,
• if you have wound healing problems after surgery,
• if you have undergone surgery.

VEGZELMA administration must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with antihypertensive medications; or in the event of a sudden and severe increase in blood pressure,
• protein in the urine accompanied by body swelling,
• a perforation in the intestinal wall,
• an abnormal communication of a tubular or fistulous type between the trachea and esophagus (the passage to the stomach), between internal organs and the skin, between the vagina and any part of the intestine or between other tissues that are normally not connected (fistula), and which your doctor considers severe,
• severe skin or deep skin layer infections,
• arterial embolism (blood clot),
• pulmonary vein embolism,
• any severe bleeding.

If you use more VEGZELMA than you should

• you may experience severe migraine. If this occurs, you must inform your doctor, pharmacist, or nurse immediately.

If you forget to use VEGZELMA

• your doctor will decide when the next dose of VEGZELMA should be administered. You must inform your doctor of this omission.

If you interrupt treatment with VEGZELMA

Stopping treatment with VEGZELMA may suppress its effect on tumor growth. Do not stop treatment with VEGZELMA unless you have consulted with your doctor.

If you have any other doubts about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

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

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

Allergic reactions

If you have an allergic reaction, consult your doctor or healthcare professional immediately. Symptoms may include: difficulty breathing or chest pain. You may also experience skin redness or flushing, rashes, chills, and tremors, dizziness or nausea, hiccups, swelling, dizziness, tachycardia, loss of consciousness.

You must seek immediate help if you experience any of the following side effects.

Severe side effects that may bevery frequent(may affect more than 1 in 10 patients) include:

• high blood pressure,
• sensation 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 to clot,
• sensation of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Severe side effects that may befrequent(may affect up to 1 in 100 patients) include:

• intestinal perforation,
• bleeding, including hemoptysis in patients with non-small cell lung cancer,
• arterial embolism,
• venous embolism,
• embolism of pulmonary vessels,
• embolism of lower limb veins,
• heart failure,
• problems with wound healing after surgery,
• skin redness, peeling, sensitivity, pain, or blisters on fingers or toes,
• decrease in the number of red blood cells,
• lack of energy,
• gastrointestinal and intestinal alterations,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced urine output or dark-colored urine,
• inflammation of the mucous membrane of the mouth and intestines, lungs, and airways, reproductive system, and urinary tract,
• mouth and esophageal ulcers that may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal pain,
• localized pus foci,
• infection, and particularly blood or urinary tract infection,
• decrease in cerebral blood flow or stroke,
• drowsiness,
• nasal bleeding,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (protein in urine),
• difficulty breathing or decreased oxygen levels in blood,
• skin or deep tissue infections,
• fistula: abnormal communication of a tubular type between internal organs and the skin or other tissues that are normally not connected, including communication between the vagina and intestine in patients with cervical cancer,
• allergic reactions (symptoms may include difficulty breathing, facial redness, skin rash, low or high blood pressure, low oxygen levels in blood, chest pain, or nausea/vomiting).

Severe side effects that may berare(may affect up to 1 in 1000 patients), include:

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

Severe side effects of unknown frequency(cannot be estimated from available data) include:

• severe skin or deep tissue infections, especially if you had intestinal perforations or problems with wound healing,
• negative effect on a woman's ability to have children (see below for more recommendations),
• brain disease with symptoms such as seizures (convulsions), headache, confusion, and vision changes (Reversible Posterior Leukoencephalopathy Syndrome or RPLS),
• symptoms suggesting changes in normal brain function (headache, vision changes, confusion, or convulsions), and high blood pressure,
• increase and weakening of the wall of a blood vessel or tearing 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 pulmonary vessels that makes the right side of the heart work harder than normal,
• perforation in the cartilage wall that separates the nasal openings,
• perforation in the stomach or intestine,
• ulcer or perforation in the stomach or small intestine lining (these symptoms may include abdominal pain, sensation of swelling, black stools, stools with blood, or blood in vomit),
• bleeding from the lower part of the large intestine,
• gum lesions, with exposed jawbone that do not heal and may be associated with pain and inflammation of surrounding tissues (see below for more recommendations),
• perforation of the gallbladder (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you experience any of these side effects mentioned, seek medical attention as soon as possible.

Side effects that arevery frequent(may affect more than 1 in 10 patients) that were not severe are:

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

Side effects that arefrequent(may affect up to 1 in 10 patients) that were not severe are:

• voice changes and hoarseness.

Patients over 65 years old have a higher risk of experiencing the following:

• embolism in the arteries that may cause stroke or heart attack,
• decrease in the number of white blood cells and platelets (which help to clot) in blood,
• diarrhea,
• unwellness,
• headache,
• fatigue,
• high blood pressure.

VEGZELMA may also cause changes in laboratory tests that your doctor will perform. These changes may include a decrease in the number of white blood cells, particularly neutrophils (a type of white blood cell that facilitates protection against infections), presence of protein in urine, decrease in potassium, sodium, or phosphorus in blood, increase in blood sugar, increase in alkaline phosphatase (an enzyme) in blood, decrease in hemoglobin (which is found in red blood cells and transports oxygen), which may be severe.

Pain in the mouth, teeth, and/or jaw, swelling, or ulcers in the mouth, numbness or heaviness of the jaw, or tooth loss. These may be signs and symptoms of jawbone damage (osteonecrosis). Immediately report to your doctor and dentist if you experience any of them.

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

VEGZELMA has been developed and manufactured to treat cancer by intravenous injection. 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,
• Eye redness, small particles or spots in vision (floaters), eye pain,
• Light flashes with floaters, progressing to partial vision loss,
• Increased intraocular pressure,
• Bleeding in the eye.

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

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

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

Do not freeze.

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

The infusion solution must be administered immediately after dilution. If it is not administered immediately, the storage times and conditions in use are the responsibility of the user and are normally not more than 24 hours 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 between 2 °C and 8 °C plus an additional 7 days between 2 °C and 30 °C.

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

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and unused medications. This will help protect the environment.

Composition of VEGZELMA

The active ingredient is bevacizumab.

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

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

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

• The other components are trehalose dihydrate, sodium phosphate, polisorbate 20, and water for injection.

Appearance of the product and contents of the package

VEGZELMA is a concentrate for solution for infusion. The concentrate is a transparent, 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

Responsible Person

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 medication by contacting the local representative of the marketing authorization holder:

Last review date of this leaflet

Other sources of information

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