Vegzelma 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

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 rapid identification of new safety information. You can help by reporting any adverse reactions you may experience. Section 4 at the end includes information on how to report these adverse reactions.

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.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, consult your doctor, pharmacist, or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents:

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

1. What Vegzelma is and what it is used for

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

Vegzelma is a medicine used to treat adult patients with advanced colorectal cancer. Vegzelma is given in combination with a chemotherapy regimen containing a fluoropyrimidine medicine.

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

Vegzelma is also used to treat adult patients with advanced non-squamous non-small cell lung cancer. Vegzelma is given together with a platinum-based chemotherapy regimen.

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

Vegzelma is also used to treat adult patients with advanced renal cell carcinoma. When used in patients with kidney cancer, it is 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 is given in combination with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, Vegzelma is 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 a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, Vegzelma is 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 is given in combination with paclitaxel and cisplatin or, alternatively, with paclitaxel and topotecan in patients who cannot receive platinum-based therapy.

2. What you need to know before Vegzelma is administered to you

Do not use Vegzelma

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

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting to use Vegzelma

• Vegzelma may increase the risk of developing perforations in the intestinal wall. If you have any condition causing inflammation in the abdomen (e.g., diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.

• Vegzelma may increase the risk of developing an abnormal passage between two organs or cavities. The risk of developing fistulas 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 surgical wound healing. You must not use this medicine if you are scheduled for surgery, have undergone major surgery within the last 28 days, or have an unhealed surgical wound.

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

• Vegzelma may increase the risk of hypertension. If you have uncontrolled high blood pressure despite medication, consult your doctor. It is important to ensure your blood pressure is under control before starting treatment with Vegzelma.

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

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

• The risk of developing blood clots or thrombi in your arteries (a type of blood vessel) may increase if you are over 65 years old, have diabetes, or have previously had arterial clots or thrombi. Consult your doctor, as these clots or thrombi may lead to heart attack or stroke.

• Vegzelma may also increase the risk of developing blood clots or thrombi in the veins (a type of blood vessel).

• This medicine may cause bleeding, especially tumor-related bleeding. Consult your doctor if you have a tendency or family history of coagulation disorders (bleeding) or if you 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 affecting your brain.

• Vegzelma may increase the risk of bleeding in your lungs, including coughing up blood or bloody sputum. Consult your doctor if you have previously experienced this.

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

• This medicine may cause infections and reduce the number of neutrophils (a type of blood cell important for protection 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 previously 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 experience headache, vision changes, confusion, or seizures (convulsions), with or without high blood pressure, consult your doctor.

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

Before starting treatment with Vegzelma or during treatment with Vegzelma:

• if you have or have had mouth, tooth, and/or jaw pain, swelling or sores in the mouth, numbness or heaviness in the jaw, or tooth loss, inform your doctor and dentist immediately.
• if you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Vegzelma, especially if you are also receiving or have received intravenous bisphosphonate injections.

Before starting treatment with Vegzelma, you may be advised to have a dental examination.

Children and adolescents

Use of Vegzelma is not recommended in children and adolescents under 18 years of age, as safety and benefit have not been established in these patients.

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

Other medicines and Vegzelma

Tell your doctor, pharmacist, or nurse if you are taking, have recently taken, or might need to take any other medicines.

Combining Vegzelma with another medicine called sunitinib maleate (used for kidney and gastrointestinal cancer) may cause serious adverse effects. Consult your doctor to ensure 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 adverse effects.

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

Pregnancy, breastfeeding, and fertility

You must not use Vegzelma if you are pregnant. Vegzelma may harm the fetus, as it can inhibit the formation of new blood vessels. Your doctor should advise you on using 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.

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

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

Driving and using machines

Vegzelma has not been shown to impair your ability to drive or operate tools or machines. However, drowsiness and fainting have been reported with the use of Vegzelma. If you experience symptoms affecting your vision or concentration, or your reaction ability, do not drive or use machines until symptoms resolve.

Vegzelma contains sodium

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

This medicine contains 0.4 mg of polysorbate 20 in each ml. Polysorbates may cause allergic reactions. Inform your doctor if you have any known allergies.

3. How to use Vegzelma

Dosage and frequency of administration

The dose of Vegzelma required depends on your body 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 appropriate dose of Vegzelma for your condition, 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 treatment until Vegzelma is no longer able to inhibit tumor growth. Your doctor will discuss these aspects with you.

Method and route of administration

Vegzelma is a concentrate for solution for infusion. Depending on the prescribed dose, either a portion 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 (a drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion may be administered over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Administration of Vegzelma must be temporarily interrupted if you:

• develop severe hypertension requiring treatment with antihypertensive medicines,
• have impaired wound healing after surgery,
• have recently undergone surgery.

Administration of Vegzelma must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with antihypertensive medicines, or if there is a sudden and severe increase in blood pressure,
• protein in the urine accompanied by body swelling,
• a perforation in the intestinal wall,
• a serious abnormal tubular or fistulous connection (fistula) between the trachea and the esophagus (the tube leading 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, as determined by your doctor,
• severe skin infections or deep skin tissue infections,
• arterial embolism (blood clot in the arteries),
• embolism in the pulmonary blood vessels,
• any severe bleeding.

If you use more Vegzelma than you should

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

If you forget to use Vegzelma

• your doctor will decide when your next dose of Vegzelma should be administered. You must inform your doctor about this missed dose.

If you stop using Vegzelma

Stopping treatment with Vegzelma may reduce its effect on tumor growth. Do not interrupt treatment with Vegzelma unless discussed with your doctor.

If you have any further questions about 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 everyone experiences them.

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if these adverse effects are not listed in this leaflet.

The adverse effects listed 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. Signs may include: difficulty breathing or chest pain. You may also experience redness or flushing of the skin or rash, chills and shivering, feeling dizzy (nausea), or feeling unwell (vomiting), swelling, dizziness, rapid heartbeat, or loss of consciousness.

You must seek immediate medical help if you experience any of the adverse effects listed below.

Serious adverse effects that may be very common (may affect more than 1 in 10 patients) include:

• high blood pressure,
• sensation of numbness or tingling in hands or feet,
• reduction in blood cell counts, including white blood cells that help fight infections (this may be accompanied by fever), and platelets that help blood to clot,
• feeling weak and lacking energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Serious adverse effects that may be common (may affect up to 1 in 100 patients) include:

• intestinal perforation,
• bleeding, including pulmonary hemorrhage in patients with non-small cell lung cancer,
• arterial blockage due to embolism,
• venous blockage due to embolism,
• blockage of blood vessels in the lungs due to pulmonary embolism,
• blockage of leg veins due to embolism,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, sensitivity, pain, or blistering on fingers or feet,
• reduction in red blood cell count,
• lack of energy,
• gastrointestinal disturbances,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced or dark-colored urine,
• inflammation of the mucosal lining of the mouth and intestine, lungs and airways, reproductive organs, and urinary tract,
• mouth sores and sores in the tube connecting the mouth to the stomach (esophagus), which may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal region pain,
• localized pus formation,
• infection, particularly blood or bladder infection,
• reduced blood supply to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (protein in urine),
• difficulty breathing or decreased oxygen levels in the blood,
• skin infections or infections of deeper layers beneath the skin,
• fistula: an abnormal tubular connection between internal organs and the skin or other tissues that are not normally connected, including connections between the vagina and intestine in patients with cervical cancer,
• allergic reactions (signs may include difficulty breathing, facial redness, skin rash, low or high blood pressure, low oxygen levels in the blood, chest pain, or nausea/vomiting).

Serious 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).

Serious adverse effects with unknown frequency (cannot be estimated from available data) include:

• severe skin infections or infections of deeper layers beneath the skin, especially if you had intestinal wall perforations or wound healing problems,
• negative effect on a woman's ability to have children (see below for further recommendations),
• brain disease with symptoms such as seizures (fits), headache, confusion, and vision disturbances (Posterior Reversible Encephalopathy Syndrome or PRES),
• symptoms suggesting changes in normal brain function (headaches, vision disturbances, confusion, or seizures), and high blood pressure,
• enlargement and weakening of the wall of a blood vessel or tear in the blood vessel wall (arterial aneurysms and dissections),
• blockage of small blood vessels in the kidney,
• abnormally high pressure in the blood vessels of the lungs causing the right side of the heart to work harder than normal,
• perforation in the cartilage wall separating the nasal openings,
• perforation of the stomach or intestine,
• ulcer or perforation in the lining of the stomach or small intestine (these signs may include abdominal pain, bloating, black stools, bloody stools, 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 (for further recommendations, see the list of adverse effects in the paragraph below),
• gallbladder perforation (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

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

Non-serious adverse effects that are very common (may affect more than 1 in 10 patients) include:

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

Non-serious adverse effects that are common (may affect up to 1 in 10 patients) include:

• changes in voice and hoarseness.

Patients over 65 years of age have an increased risk of experiencing the following:

• arterial embolism that may lead to stroke or heart attack,
• reduction in white blood cell and platelet counts (which help with blood clotting),
• diarrhea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

Vegzelma may also cause changes in laboratory tests performed by your doctor. These changes may include a reduction in white blood cell counts, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in the urine, decreased levels of potassium, sodium, or phosphorus in the blood, increased blood sugar, increased alkaline phosphatase (an enzyme) in the blood, decreased hemoglobin (found in red blood cells and responsible for oxygen transport), which may be severe.

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

Premenopausal women (women who have menstrual periods) may notice that their periods become irregular or stop, and may experience fertility problems. If you are considering having children, discuss this with your doctor before starting treatment.

Vegzelma has been developed and manufactured for cancer treatment via injection into the bloodstream. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for this use. When bevacizumab is injected directly into the eye (off-label use), the following side effects may occur:

• Eye infection or inflammation of the eyeball,
• Eye redness, small particles or spots in vision (floaters), eye pain,
• Seeing flashes of light with floaters, progressing to partial vision loss,
• Increased intraocular pressure,
• Bleeding in the eye.

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 can also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide 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 expiry date stated on the carton and label of the vial after EXP. The expiry date refers to 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 infusion solution should be administered immediately after dilution. If immediate administration is not possible, the storage times and conditions during use are the responsibility of the user and normally should not exceed 24 hours at between 2 °C and 8 °C, unless the infusion solutions have been prepared under sterile conditions. When dilution has been carried out under sterile conditions, Vegzelma remains stable for 60 days at between 2 °C and 8 °C plus an additional 7 days at between 2 °C and 30 °C.

Do not use Vegzelma if you notice any foreign particles or discoloration prior to administration.

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

6. Package contents and other information

Composition of Vegzelma

The active substance 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 components are trehalose dihydrate, sodium phosphate, polysorbate 20, and water for injections.

Appearance of the medicinal product and contents of the container

Vegzelma is a concentrate for solution for infusion. The concentrate is a clear, colourless 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 Vegzelma pack contains 1 vial, 2 vials or 10 vials.

Marketing Authorisation Holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B tower

Hungary

Manufacturer

Nuvisan GmbH

Wegenerstraße 13

89231 Neu-Ulm

Germany

Nuvisan France SARL

2400, Route des Colles

06410, Biot

France

Kymos S.L.

Ronda Can Fatjó 7B

(Parc Tecnològic del Vallès) Cerdanyola del Vallès

08290 Barcelona

Spain

Midas Pharma GmbH

Rheinstraße 49

55218 Ingelheim am Rhein

Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Date of the most recent revision of this leaflet <{MM/YYYY}>

Other sources of information

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