ZIRABEV 25 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Zirabev 25mg/ml concentrate for solution for infusion

bevacizumab

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

1. What is Zirabev and what is it used for

Zirabev contains the active substance 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 lining of blood and lymphatic vessels in the body. The VEGF protein causes blood vessels to grow into tumors, these blood vessels provide nutrients and oxygen to the tumor. Once bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels that provide nutrients and oxygen to the tumor.

Zirabev is a medicine used to treat adult patients with advanced cancer in the large intestine, i.e., in the colon or rectum. Zirabev will be given in combination with a chemotherapy treatment that contains a fluoropyrimidine medicine.

Zirabev 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.

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

Zirabev is 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). Zirabev will be given in combination with erlotinib.

Zirabev 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.

Zirabev is 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 a recurrence of their disease at least 6 months after they were last treated with a platinum-based chemotherapy regimen, Zirabev 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 a recurrence of their disease at least 6 months after they were last treated with a platinum-based chemotherapy regimen, Zirabev will be given in combination with paclitaxel or topotecan, or pegylated liposomal doxorubicin.

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

2. What you need to know before you use Zirabev

Do not use Zirabev

• if you are allergic to bevacizumab or any of the other ingredients of this medicine (listed in section 6);
• if you are allergic 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 Zirabev

• Your doctor should record the trade name and batch number of your medicine.

• Zirabev may increase the risk of developing holes in the wall of the intestine. If you have any condition that causes inflammation in the abdomen (e.g., diverticulitis, stomach ulcers, chemotherapy-induced colitis), talk to your doctor.

• Zirabev may increase the risk of developing a connection or passage between two organs or blood 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 increase the risk of problems with wound healing after surgery. If you are going to have an operation, if you have had major surgery in the last 28 days, or if you still have an open wound after surgery, you should not receive this medicine.

• Zirabev may increase the risk of developing serious infections of the skin or deeper layers under the skin, especially if you have holes in the wall of the intestine or problems with wound healing.

• Zirabev may increase the risk of high blood pressure. If you have high blood pressure that is not adequately controlled with blood pressure medicines, talk to your doctor, as it is important to make sure your blood pressure is under control before starting treatment with Zirabev.

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

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

• The risk of developing blood clots 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 in your arteries before. Talk to your doctor, as blood clots can lead to a heart attack and stroke.

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

• This medicine may cause bleeding, especially bleeding related to the tumor. Talk to your doctor if you or your family members tend to have bleeding problems or if you are taking medicines to thin your blood for any reason.

• Zirabev may cause bleeding in and around your brain. Talk to your doctor if you have metastatic cancer that affects your brain.

• Zirabev may increase the risk of bleeding in the lungs, including coughing up or spitting up blood. Talk to your doctor if you have noticed this before.

• Zirabev may increase the risk of heart problems. It is important that you tell your doctor if you have ever received anthracyclines (e.g., doxorubicin, a specific type of chemotherapy used to treat some types of cancer), if you have received radiation therapy to the chest, or if you have any heart disease.

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

• Zirabev may cause hypersensitivity (including anaphylactic reactions) and/or infusion reactions (reactions related to the injection of the medicine). Tell your doctor, pharmacist, or nurse if you have experienced problems after an injection, 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 bevacizumab treatment. If you have a headache, changes in vision, confusion, or seizures with or without high blood pressure, contact your doctor.

Talk to your doctor, even if any of the above situations have only happened to you in the past.

Before you receive Zirabev or during treatment with Zirabev:

You may be advised to have a dental check-up before you start treatment with Zirabev.

Children and adolescents

Zirabev is not recommended for use in children and adolescents under 18 years of age because safety and efficacy have not been established in these patients.

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

Other medicines and Zirabev

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

The combination of Zirabev with another medicine called sunitinib malate (prescribed for kidney and gastrointestinal cancer) may cause serious side effects. Talk to your doctor to make sure you do not combine these medicines.

Tell your doctor if you are using platinum-based or taxane-based treatments for metastatic breast or lung cancer. These treatments in combination with Zirabev 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

You must not use this medicine if you are pregnant. Zirabev may harm your unborn baby, as it may stop the formation of new blood vessels. Your doctor will advise you to use contraceptive methods during treatment with Zirabev and for at least 6 months after the last dose of Zirabev.

Tell your doctor immediately if you are pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future.

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

Zirabev may affect female fertility. Talk to your doctor for more information.

Talk to your doctor, pharmacist, or nurse before taking any medicine.

Driving and using machines

Bevacizumab 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 bevacizumab. If you experience symptoms that affect your vision or concentration, or your ability to react, do not drive or use machines until the symptoms disappear.

Zirabev contains sodium

This medicine contains 3.0 mg of sodium (a major component of cooking/table salt) in each 4 ml vial. This is equivalent to 0.15% of the maximum recommended daily intake of sodium for an adult.

This medicine contains 12.1 mg of sodium (a major component of cooking/table salt) in each 16 ml vial. This is equivalent to 0.61% of the maximum recommended daily intake of sodium for an adult.

Depending on your body weight and your dose of Zirabev, you may receive several vials. This should be taken into account if you are on a low-salt diet.

3. How to use Zirabev

Dose and frequency of administration

The dose of Zirabev 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 dose of Zirabev that is right for you. You will receive Zirabev once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to treatment and should continue to receive this medicine until Zirabev no longer stops the growth of the tumor. Your doctor will discuss this with you.

Form and route of administration

Zirabev is a concentrate for solution for infusion. According to the dose you have been prescribed, a fraction or all of the contents of the Zirabev vial will be diluted with a sodium chloride solution before use. A doctor or nurse will give you this diluted Zirabev solution by intravenous infusion (by drip into a vein). The first infusion will be given over 90 minutes. If you tolerate it well, the second infusion can be given over 60 minutes. Later infusions can be given over 30 minutes.

Zirabev administration should be temporarily interrupted:

• if you develop severe high blood pressure that requires treatment with blood pressure medicines;
• if you have problems with wound healing after surgery;
• if you have had surgery.

Zirabev administration should be permanently stopped if you develop:

• severe high blood pressure that cannot be controlled with blood pressure medicines; or if you have a sudden and severe increase in blood pressure;
• protein in the urine accompanied by swelling of the body;
• a hole in the wall of the intestine;
• a connection or passage between the trachea and esophagus, between internal organs and the skin, between the vagina and any part of the intestine, or between other tissues that are not normally connected (fistula) that your doctor considers serious;
• serious infections of the skin or deeper layers under the skin;
• a blood clot in the arteries;
• a blood clot in the blood vessels of the lungs;
• any serious bleeding.

If you use more Zirabev than you should

• You may develop a severe migraine. If this happens, you should talk to your doctor, pharmacist, or nurse immediately.

If you forget to use Zirabev

• Your doctor will decide when you should receive your next dose of Zirabev. Talk to your doctor about this.

If you stop treatment with Zirabev

Stopping treatment with Zirabev may stop its effect on tumor growth. Do not stop treatment with Zirabev unless you have talked to 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 any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is an adverse effect that is not listed in this prospectus.

The adverse effects listed below have been observed when bevacizumab was administered in combination with chemotherapy. This does not necessarily mean that these adverse effects were caused exclusively by bevacizumab.

Allergic Reactions

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

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

The serious adverse effects that may be very common(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, which help fight infections (this may be accompanied by fever), and platelets, which help blood clot,
• feeling of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

The serious adverse effects that may be common(may affect up to 1 in 10 patients) include:

• intestinal perforation,
• bleeding, including hemorrhage in the lungs in patients with non-small cell lung cancer,
• blockage of the arteries by a blood clot,
• blockage of the veins by a blood clot,
• blockage of the blood vessels in the lungs by a blood clot,
• blockage of the veins in the legs by a blood clot,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, pain to the touch, pain, or blisters on the fingers or toes,
• decrease in the number of red blood cells in the blood,
• lack of energy,
• stomach and intestine disorders,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced or dark urine output,
• inflammation of the mucous membrane 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 abscesses,
• 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 low oxygen levels in the blood,
• skin or deep tissue infections,
• fistula: abnormal tubular connection or passage 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).

The serious adverse effects that may be rare(may affect up to 1 in 1,000 patients) include:

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

The serious adverse effects of unknown frequency(cannot be estimated from the available data) include:

• severe skin or deep tissue infections, especially if there were intestinal perforations or wound healing problems,
• a negative effect on a woman's ability to have children (see the paragraphs below the list of adverse effects for more recommendations),
• a brain condition with symptoms including seizures (attacks), headache, confusion, and vision changes (posterior reversible encephalopathy syndrome or PRES),
• symptoms indicating changes in normal brain function (headaches, vision changes, 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 more 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 (see the paragraphs below the list of adverse effects for more recommendations),
• perforation of the gallbladder (the symptoms and signs may include abdominal pain, fever, and nausea/vomiting).

You should seek medical attention as soon as possible if you suffer from any of the adverse effects mentioned below.

The adverse effects that are very common(may affect more than 1 in 10 patients) that are not serious include:

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

The adverse effects that are common(may affect up to 1 in 10 patients) that are not serious include:

• changes in voice and hoarseness.

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

• blood clot in the arteries that can cause a stroke or heart attack,
• decrease in the number of white blood cells in the blood and in the cells that help blood clot,
• diarrhea,
• nausea,
• headache,
• fatigue,
• high blood pressure.

Zirabev may also cause changes in laboratory tests that your doctor performs. These include a reduced number of white blood cells in the blood, in particular neutrophils (a type of white blood cell that helps protect against infections) in the blood; presence of protein in the urine; decrease in potassium, sodium, or phosphorus (a mineral) in the blood; increase in blood sugar; increase in alkaline phosphatase (an enzyme) in the blood; increase in serum creatinine (a protein that is evaluated in a blood test to see how well the kidneys are working); decrease in hemoglobin (a protein found in red blood cells that carries oxygen), which can be serious.

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

Women of childbearing potential (women who have a menstrual cycle) may notice that their periods become irregular or disappear and may experience a decrease in fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.

Zirabev has been developed and manufactured to treat cancer by injecting it 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 Zirabev 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 vision (floaters), eye pain,
• vision of flashes of light with floaters, progressing to loss of some vision,
• increased eye pressure,
• bleeding in the eye.

Reporting of Adverse Effects

If you experience adverse effects, consult your doctor, pharmacist, or nurse, even if it is an adverse effect that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Zirabev

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

Do not use this medicine after the expiration date that appears on the outer packaging and on the label of the vial after EXP. 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 used immediately, the time and conditions of storage in use will be the responsibility of the user and will normally not exceed 24 hours between 2°C and 8°C, unless the infusion solutions have been prepared in a sterile environment. When dilution takes place in a sterile environment, Zirabev will be stable after dilution for a period of up to 35 days stored between 2°C and 8°C after dilution and for a period of up to 48 hours at temperatures that do not exceed 30°C.

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

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

6. Package Contents and Additional Information

Composition of Zirabev

• The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab.

Each 4 ml vial contains 100 mg of bevacizumab.

Each 16 ml vial contains 400 mg of bevacizumab.

• The other ingredients are sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide (for pH adjustment), and water for injectable preparations (see section 2, "Zirabev contains sodium").

Appearance of the Product and Package Contents

Zirabev is a concentrate for solution for infusion. The concentrate is a colorless to light brown liquid and transparent to slightly opalescent in a glass vial with a rubber stopper. Each vial contains 100 mg of bevacizumab in 4 ml of solution or 400 mg of bevacizumab in 16 ml of solution. Each package of Zirabev contains one vial.

Marketing Authorization Holder

Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium

Manufacturer

Pfizer Service Company BV, Hoge Wei 10, Zaventem, 1930, Belgium

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

Spain

Pfizer, S.L.

Tel: +34 91 490 99 00

Date of the Last Revision of this Prospectus:11/2023

Other Sources of Information

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