Label: information for the user

Zirabev 25mg/ml concentrate for solution for infusion

bevacizumab

Read this label carefully before starting to use this medicine, because it contains important information for you.

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

Zirabev is a medication used for the treatment of adult patients with advanced cancer in the large intestine, that is, in the colon or rectum. Zirabev will be administered in combination with a chemotherapy regimen containing a fluoropyrimidine medication.

Zirabev 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.

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

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

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

Zirabev is used for the treatment of adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. When used in patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, it will be administered in combination with carboplatin and paclitaxel.

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

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

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

No use Zirabev

• if you are allergic to bevacizumab or any of the other components of this medication (listed in section6);
• if you are allergic to products derived from Chinese hamster ovary cells (CHO) or other recombinant human or humanized antibodies;
• if you are pregnant.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Zirabev

• Your doctor must record the brand name and batch number of your medication.

• Zirabev may increase the risk of presenting perforations in the intestinal wall. If you have any condition that causes inflammation in the abdomen (e.g., diverticulitis, stomach ulcers, chemotherapy-induced colitis), consult your doctor.

• Zirabev may increase the risk of presenting an abnormal connection or passage between two organs or blood vessels. The risk of presenting connections 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 increase the risk of problems with wound healing after surgery. If you are about to undergo surgery, if you have had major surgery in the last 28days, or if you still have an open wound after surgery, do not receive this medication.

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

• Zirabev may increase the incidence of high blood pressure. If you have uncontrolled high blood pressure, consult your doctor, as it is essential to ensure that your blood pressure is under control before starting treatment with Zirabev.

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

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

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

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

• This medication may produce bleeding, especially tumor-related bleeding. Consult your doctor if you or your family tend to experience bleeding problems or if you are taking medications to thin your blood for any reason.

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

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

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

• This medication may produce infections and decrease the number of neutrophils (an important type of blood cell for protection against bacteria).

• Zirabev may produce hypersensitivity (including anaphylactic reactions) and/or infusion reactions (reactions related to the injection of the medication). Inform your doctor, pharmacist, or nurse if you have experienced problems after an injection, such as dizziness/dizziness, difficulty breathing, swelling, or skin rash.

• A rare neurological adverse effect called reversible posterior leukoencephalopathy syndrome (RPLS) has been associated with bevacizumab treatment. If you have headaches, vision changes, confusion, or seizures with or without high blood pressure, contact your doctor.

Consult your doctor, even if any of the above situations have only occurred in the past.

Before receiving Zirabev or during treatment with Zirabev:

• if you have or have had mouth, tooth, and/or jaw pain, swelling, or sores inside your mouth, numbness, or a feeling of heaviness in your jaw, or if a tooth has become loose, inform your doctor and dentist immediately;
• if you need to undergo invasive dental treatment or surgery, inform your dentist that you are receiving Zirabev, especially when you are also receiving or have received an intravenous bisphosphonate.

You may be recommended to have a dental check-up before starting treatment with Zirabev.

Children and adolescents

Zirabev is not recommended for use in children and adolescents under 18years old because 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 18years old treated with bevacizumab.

Other medications and Zirabev

Inform your doctor, pharmacist, or nurse if you are taking, have taken recently, or may need to take any other medication.

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

Inform your doctor if you are using platinum-based or taxane treatments for metastatic breast or lung cancer. These treatments in combination with Zirabev may increase the risk of severe adverse effects.

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

Pregnancy, breastfeeding, and fertility

You should not use this medication if you are pregnant. Zirabev may harm the fetus, as it may stop the formation of new blood vessels. Your doctor will recommend that you use contraceptive methods during treatment with Zirabev and for at least 6months after the last dose of Zirabev.

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

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

Zirabev may affect female fertility. Consult your doctor for more information.

Consult your doctor, pharmacist, or nurse before taking any medication.

Driving and operating machinery

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

Zirabev contains sodium

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

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

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

Dosage and Administration Frequency

The dose of Zirabev required depends on your weight and the type of cancer being treated. The recommended dose is 5mg, 7.5mg, 10mg or 15mg per kilogram of body weight. Your doctor will prescribe the appropriate dose of Zirabev for you. You will receive Zirabev once every 2 or 3weeks. The number of infusions you receive will depend on how you respond to treatment and you should continue receiving this medication until Zirabev no longer stops tumor growth. Your doctor will discuss this with you.

Form and Route of Administration

Zirabev is a concentrate for solution for infusion. Depending on the dose prescribed, a fraction or the entire contents of the Zirabev vial will be diluted with a sodium chloride solution before use. A doctor or nurse will administer this diluted Zirabev solution via intravenous infusion (drip in a vein). The first infusion will be administered for 90minutes. If tolerated well, the second infusion may be administered for 60minutes. Subsequent infusions may be administered for 30minutes.

Zirabev Administration Should be Temporarily Interrupted:

• if you experience severe high blood pressure requiring treatment with blood pressure medications;
• if you have wound healing problems after a surgical procedure;
• if you have undergone a surgical procedure.

Zirabev Administration Should be Permanently Discontinued if You Experience:

• severe high blood pressure that cannot be controlled with blood pressure medications, or in the event of a sudden and severe increase in blood pressure;
• proteinuria accompanied by body swelling;
• intestinal perforation;
• an abnormal connection or passage, such as a fistula, 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 normally not connected, and which your doctor considers severe;
• severe skin or deeper tissue infections;
• arterial thrombosis;
• pulmonary vascular thrombosis;
• any severe bleeding.

If You Take More Zirabev Than You Should

• You may experience severe migraine. If this happens, you should consult your doctor, pharmacist, or nurse immediately.

If You Forget to Use Zirabev

• Your doctor will decide when the next dose of Zirabev should be administered. Consult with your doctor.

If You Interrupt Zirabev Treatment

Interrupting Zirabev treatment may stop its effect on tumor growth. Do not interrupt Zirabev treatment unless you have consulted with your doctor.

If you have any other questions 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 any type of side effect, consult your doctor, pharmacist or nurse, even if it is a side effect that does not appear in this leaflet.

The side effects listed below were observed when bevacizumab was administered in combination with chemotherapy. This does not necessarily mean that these side 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 skin redness or flushing, rashes, chills, and tremors, nausea or vomiting, swelling, dizziness, tachycardia, and loss of consciousness.

You must seek medical attention immediately if you experience any of the following side effects.

The serious side effects that may bevery common(may affect more than 1 in 10patients) include:

• high blood pressure,
• numbness or tingling in the 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 to clot,
• feeling of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

The serious side effects that may becommon(may affect up to 1 in 10patients) include:

• intestinal perforation,
• bleeding, including pulmonary hemorrhage in patients with non-small cell lung cancer,
• arterial thromboembolism,
• venous thromboembolism,
• pulmonary embolism,
• deep vein thrombosis,
• heart failure,
• problems with wound healing after surgery,
• erythema, desquamation, pain on palpation, pain or blisters on the fingers or toes,
• decrease in red blood cell count,
• lack of energy,
• gastrointestinal disorders,
• muscle and joint pain, muscle weakness,
• xerostomia combined with thirst and/or reduced urine output or dark urine,
• inflammation of the mucous membranes of the mouth and intestine, lungs and respiratory tract, reproductive system, and urinary tract,
• mouth ulcers and esophageal ulcers that may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal pain,
• localized pus-filled lesions,
• infection, and particularly sepsis or urinary tract infection,
• decrease in cerebral blood flow or stroke,
• drowsiness,
• epistaxis,
• tachycardia,
• intestinal obstruction,
• abnormal urine analysis (protein in urine),
• difficulty breathing or low oxygen levels in the blood,
• skin or subcutaneous tissue infections,
• fistula: abnormal communication or passage 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 (the signs may include difficulty breathing, facial flushing, skin rash, low blood pressure or high blood pressure, low oxygen levels in the blood, chest pain or nausea/vomiting).

The serious side effects that may berare(may affect up to 1 in 10,000patients) include:

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

The serious side effects of unknown frequencycannot be estimated(cannot be estimated from available data) include:

• severe skin or subcutaneous tissue infections, especially if you had intestinal perforation or wound healing problems,
• negative effect on the woman's ability to have children (see the paragraphs below the list of side effects for more recommendations),
• cerebral syndrome with symptoms that include seizures (convulsions), headache, confusion, and visual disturbances (reversible posterior leukoencephalopathy syndrome or RPLS),
• symptoms indicating changes in normal brain function (headache, visual disturbances, confusion, or convulsions) and high blood pressure,
• aneurysm or arterial dissection (tearing of the blood vessel wall).
• renal microvascular obstruction,
• abnormally high blood pressure in the pulmonary arteries that makes the right side of the heart work harder,
• perforation of the nasal septum cartilage,
• perforation of the stomach or intestine,
• ulcer or perforation of the stomach or small intestine lining (these signs may include abdominal pain, feeling of swelling, black stools, stools with blood, or blood in the vomit),
• hemorrhage of the lower part of the large intestine,
• gingival lesions with exposed jawbone that do not heal and may be associated with pain and inflammation of surrounding tissues (see the paragraphs below the list of side effects for more recommendations),
• perforation of the gallbladder (the symptoms and signs may include abdominal pain, fever, and nausea/vomiting).

You must seek medical attention as soon as possible if you experience any of the following side effects.

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

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

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

• voice changes and hoarseness.

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

• arterial thromboembolism that may cause stroke or heart attack,
• decrease in white blood cell count and platelet count,
• diarrhea,
• nausea,
• headache,
• fatigue,
• high blood pressure.

Zirabev may also cause changes in laboratory tests that your doctor will perform. These include a reduced number of white blood cells in the blood, particularly 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 phosphate (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 transports oxygen), which may be serious.

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

Pre-menopausal women may notice that their menstrual cycles 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 was 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:

Reporting of side effects

If you experience side effects, consult your doctor, pharmacist, or nurse, even if it is a side effect that does not appear in this leaflet. You can also report them directly through theSistema Español de Farmacovigilancia de Medicamentos de Uso Humano:www.notificaRAM.es. 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 outer packaging and on the vial label after EXP. 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 not used immediately, the time and storage conditions in use will be the responsibility of the user and are normally not greater than 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 remain stable after dilution for a period of up to 35 days stored between 2°C and 8°C after dilution and for a period up to 48 hours at temperatures not exceeding 30°C.

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

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of Zirabev

• The active ingredient is bevacizumab. Each milliliter of concentrate contains 25 mg of bevacizumab.

Each vial of 4 ml contains 100 mg of bevacizumab.

Each vial of 16 ml contains 400 mg of bevacizumab.

• The other components are sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide (for pH adjustment) and water for injection (see section 2, “Zirabev contains sodium”).

Appearance of the product and contents of the packaging

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 Bruxelles, Belgium

Responsible for Manufacturing

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

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

Spain

Pfizer, S.L.

Phone: +34 91 490 99 00

Last review date of this leaflet: 11/2023

Other sources of information

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