Zirabev 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Zirabev 25mg/ml concentrate for solution for infusion

bevacizumab

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, consult 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.

Contents of the leaflet

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

1. What Zirabev is and what it is used for

Zirabev contains the active substance bevacizumab, a humanized 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 lining of blood and lymphatic vessels in the body. The VEGF protein promotes the growth of blood vessels into tumors; these blood vessels supply nutrients and oxygen to the tumor. By binding to VEGF, bevacizumab inhibits tumor growth by blocking the formation of new blood vessels that supply nutrients and oxygen to the tumor.

Zirabev is a medicine used to treat adult patients with advanced colorectal cancer, that is, cancer of the colon or rectum. Zirabev is given in combination with a chemotherapy regimen containing a fluoropyrimidine medicine.

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

Zirabev is also used to treat adult patients with advanced non-small cell lung cancer. Zirabev is given in combination with a platinum-containing chemotherapy regimen.

Zirabev 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). In these patients, Zirabev is given in combination with erlotinib.

Zirabev is also used to treat adult patients with advanced renal cell carcinoma (kidney cancer). When used in patients with kidney cancer, Zirabev is administered together with another type of medicine called interferon.

Zirabev 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, Zirabev is administered in combination with carboplatin and paclitaxel.

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, Zirabev is administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.

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, Zirabev is administered 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 is administered 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 using 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 to other recombinant human or humanized antibodies;
• if you are pregnant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with Zirabev.

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

• Zirabev 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 ulcers, chemotherapy-induced colitis), consult your doctor.

• Zirabev may increase the risk of developing an abnormal connection or passage between two organs or blood vessels. The risk of developing connections 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 complications with wound healing after surgery. You must not receive this medicine if you are scheduled for surgery, if you have undergone major surgery within the last 28 days, or if you still have an unhealed surgical wound.

• Zirabev may increase the risk of serious skin infections or infections in deeper layers beneath the skin, especially if you have intestinal wall perforations or impaired wound healing.

• This medicine may increase the incidence of high blood pressure. If you have uncontrolled high blood pressure despite treatment with antihypertensive medications, consult your doctor, as it is important to ensure your blood pressure is under control before starting treatment with Zirabev.

• 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 appearing 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, have diabetes, or have previously had arterial blood clots. Consult your doctor, as blood clots can lead to 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, particularly tumor-related bleeding. Consult your doctor if you or your family have a history of bleeding disorders or if you are taking any blood-thinning medications for any reason.

• Zirabev may cause bleeding in and around your brain. Consult your doctor if you have metastatic cancer affecting your brain.

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

• Zirabev may increase the risk of heart weakening. It is important to inform your doctor if you have ever received anthracyclines (e.g., doxorubicin, a specific type of chemotherapy used to treat certain cancers), if you have received chest radiotherapy, or if you have any heart disease.

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

• Zirabev may cause hypersensitivity (including anaphylactic reactions) and/or infusion-related reactions (reactions related to the injection of the medicine). Inform your doctor, pharmacist, or nurse if you have previously 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 experience headache, vision changes, confusion, or seizures with or without high blood pressure, contact your doctor immediately.

Talk to your doctor even if any of the conditions listed above occurred only in the past.

Before receiving Zirabev or during treatment with Zirabev:

• if you have or have had mouth pain, teeth and/or jaw pain, swelling or sores inside the mouth, numbness or a heavy sensation in the jaw, or loose teeth, inform your doctor and dentist immediately;
• if you need invasive dental treatment or dental surgery, inform your dentist that you are receiving Zirabev, especially if you are also receiving or have received an intravenous bisphosphonate injection.

You may be advised 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 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 Zirabev

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

Combining Zirabev with another medicine called sunitinib malate (used for kidney and gastrointestinal cancer) may cause serious adverse effects. Consult your doctor to ensure you do not combine these medicines.

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

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

Pregnancy, breastfeeding, and fertility

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

Inform 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 during treatment with Zirabev and for at least 6 months after the last dose of Zirabev, as this medicine may interfere with your baby's growth and development.

Zirabev may affect female fertility. Consult your doctor for further 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 operate tools or machinery. However, drowsiness and fainting have been reported with bevacizumab use. If you experience symptoms affecting your vision, concentration, or reaction ability, do not drive or use machines until symptoms resolve.

Zirabev contains sodium and polysorbate 80

Sodium

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

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

Depending on your body weight and Zirabev dose, you may receive multiple vials. This should be considered if you are on a low-salt diet.

Polysorbate

This medicine contains 0.8 mg of polysorbate 80 in each 100 mg/4 ml vial and 3.2 mg in each 400 mg/16 ml vial, equivalent to 0.2 mg/ml. Polysorbates may cause allergic reactions. Inform your doctor if you have any known allergies.

3. How to use Zirabev

Dosage and frequency of administration

The required dose of Zirabev 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 appropriate dose of Zirabev for you. You will receive Zirabev once every 2 or 3 weeks. The number of infusions you receive will depend on your response to treatment, and you should continue receiving this medicine until Zirabev no longer controls tumor growth. Your doctor will discuss this with you.

Method and route of administration

Zirabev is a concentrate for solution for infusion. Depending on the prescribed dose, part or all of the contents of the Zirabev vial will be diluted with sodium chloride solution before use. A doctor or nurse will administer this diluted Zirabev solution as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If you tolerate it well, the second infusion may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Administration of Zirabev must be temporarily interrupted:

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

Administration of Zirabev must be permanently discontinued if you experience:

• severe high blood pressure that cannot be controlled with blood pressure medications; or if there is a sudden and severe increase in blood pressure;
• presence of protein in the urine accompanied by body swelling;
• a perforation in the intestinal wall;
• an abnormal tubular 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 normally not connected (fistula), which your doctor considers serious;
• severe skin infections or severe infections of deeper layers beneath the skin;
• an arterial blood clot;
• a blood clot in the blood vessels of the lungs;
• any severe bleeding.

If you use more Zirabev than you should

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

If you forget to use Zirabev

• Your doctor will decide when your next dose of Zirabev should be administered. Please discuss this with your doctor.

If you stop treatment with Zirabev

Stopping treatment with Zirabev may halt its effect on tumor growth. Do not discontinue treatment with Zirabev 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 gets them.

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

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 solely caused by bevacizumab.

Allergic reactions

If you have an allergic reaction, inform your doctor or a 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, and loss of consciousness.

You must seek immediate medical attention if you experience any of the following adverse effects.

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

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

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

• perforation of the intestine,
• bleeding, including pulmonary haemorrhage in patients with non-small cell lung cancer,
• blockage of arteries by a blood clot,
• blockage of veins by a blood clot,
• blockage of blood vessels in the lungs by a blood clot,
• blockage of leg veins by a blood clot,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, tenderness, pain, or blisters on fingers or feet,
• decrease in the number of red blood cells in the blood,
• lack of energy,
• stomach and intestinal disorders,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced amount of dark-coloured urine,
• inflammation of the moist linings 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, which may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal region pain,
• localized areas of pus,
• infection, and particularly infection in the blood or bladder,
• reduced blood supply to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (proteins in the urine),
• difficulty breathing or low oxygen levels in the blood,
• skin infections or infections of deeper layers beneath the skin,
• fistula: an abnormal tubular connection or passage between internal organs and the skin or other tissues that are not normally connected, including connections between the vagina and the intestine in patients with cervical cancer,
• allergic reactions (signs may include difficulty breathing, facial redness, skin rash, low blood pressure 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 1,000 patients) include:

• severe, sudden 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:

• serious infections of the skin or deeper layers beneath the skin, especially if you had perforations in the intestinal wall or problems with wound healing,
• a negative effect on a woman’s ability to have children (see paragraphs following the list of adverse effects for further recommendations),
• a brain condition with symptoms including seizures (fits), 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,
• enlargement and weakening of the wall of a blood vessel or tearing of the blood vessel wall (aneurysms and arterial dissections),
• blockage of small blood vessels in the kidney,
• abnormally high blood 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 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, 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 (see paragraphs following the list of adverse effects for further recommendations),
• gallbladder perforation (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 adverse effects.

Very common adverse effects (may affect more than 1 in 10 patients) that were not serious include:

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

Common adverse effects (may affect up to 1 in 10 patients) that were not serious include:

• changes in voice and hoarseness.

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

• blood clot in arteries, which may lead to stroke or heart attack,
• reduction in the number of white blood cells in the blood and in cells that help blood to clot,
• diarrhoea,
• nausea,
• headache,
• fatigue,
• high blood pressure.

Zirabev may also cause changes in laboratory tests performed by your doctor. 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); presence of proteins in the urine; decreased levels of potassium, sodium, or phosphorus (a mineral) in the blood; increased blood sugar; increased alkaline phosphatase (an enzyme) in the blood; increased serum creatinine (a protein measured in a blood test to assess kidney function); decreased haemoglobin (a protein found in red blood cells that carries oxygen), which may be severe.

Pain in the mouth, teeth, and/or jaw, swelling or sores inside the mouth, numbness or heaviness in the jaw, or loose teeth. These could be signs and symptoms of bone damage in the jaw (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 reduced 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 injection into the bloodstream. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for use in this way. When Zirabev is injected directly into the eye (unauthorized 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,
• seeing flashes of light with floaters, progressing to partial vision loss,
• increased eye pressure,
• bleeding in the eye.

Reporting of adverse effects

If you experience any adverse effects, talk to your doctor, pharmacist, or nurse, even if they are effects 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 Zirabev

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

Do not use this medicine after the expiry date stated on the outer packaging and on the 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 not used immediately, the storage time and conditions during use are the responsibility of the user and normally should not exceed 24 hours between 2 °C and 8 °C, unless the infusion solutions are prepared under sterile conditions. When dilution takes place under sterile conditions, Zirabev is stable after dilution for up to 35 days when stored between 2 °C and 8 °C after dilution, and for up to 48 hours at temperatures not exceeding 30 °C.

Do not use Zirabev if particles or discoloration are observed before administration.

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

6. Contents of the pack and other 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 components are sucrose, succinic acid, disodium edetate, polysorbate 80 (E 433), sodium hydroxide (for pH adjustment) and water for injections (see section 2, “Zirabev contains sodium and polysorbate 80”).

Nature of the product and contents of the pack

Zirabev is a concentrate for solution for infusion. The concentrate is a colourless to light brown, clear to slightly opalescent liquid 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 pack of Zirabev contains one vial.

Marketing Authorisation Holder

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

Manufacturer

Pfizer Service Company BV, Hermeslaan 11, 1932 Zaventem, Belgium

Further information on this medicinal product is available from the local representative of the Marketing Authorisation Holder.

Date of the most recent review of this leaflet:

Other sources of information

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