25 mg/ml concentrate for infusion solution
bevacizumab
What Zirabev is and what it is used for
Zirabev contains the active ingredient bevacizumab, which is a humanized monoclonal antibody (a type of protein normally made by the immune system to help protect the body against infection and cancer). Bevacizumab binds selectively to a protein called VEGF ( human vascular endothelial growth factor), which is found inside the body’s blood and lymph vessels. The VEGF protein causes blood vessels to grow in the tumor and these blood vessels supply the tumor with nutrients and oxygen. When bevacizumab is bound to VEGF, it prevents tumor growth by blocking the growth of the blood vessels that supply tumor one with nutrients and oxygen.
Zirabev is a medicine used to treat adult patients with advanced cancer of the colon or rectum. Zirabev is given together with chemotherapy containing fluoropyrimidine.
Zirabev is also used to treat adult patients with metastatic (spread) breast cancer. When used in patients with breast cancer, it will be given together with a chemotherapy drug called paclitaxel or capecitabine.
Zirabev is also used to treat adult patients with advanced non-small cell lung cancer. Zirabev is then given together with chemotherapy containing platinum.
Zirabev is also used to treat adult patients with advanced non-small cell lung cancer when the cancer cells have a specific mutation in a protein called epidermal growth factor receptor (EGFR). Zirabev is then given together with erlotinib.
Zirabev is also used to treat adult patients with advanced kidney cancer. When Zirabev is used in patients with kidney cancer, it will be given together with another type of medicine called interferon.
Zirabev is also used to treat adult patients with an advanced ovarian, fallopian tube, or primary peritoneal cancer. When treating patients with an ovarian, fallopian tube, or primary peritoneal cancer, Zirabev should be given in combination with carboplatin and paclitaxel.
When used in adult patients with an advanced ovarian, fallopian tube, or primary peritoneal cancer whose disease has come back at least 6 months after they were last treated with a platinum-containing chemotherapy, Zirabev will be given in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.
When used in adult patients with an advanced ovarian, fallopian tube, or primary peritoneal cancer whose disease has returned earlier than 6 months after the last time they were treated with a platinum-containing chemotherapy agent,
Zirabev is to be given in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.
Zirabev is also used to treat adult patients with residual, recurrent, or metastatic cervical cancer. Zirabev is then given in combination with paclitaxel and cisplatin, alternatively paclitaxel and topotecan in patients who cannot receive platinum treatment.
What you need to know before you use Zirabev
Do not use Zirabev
- if you are allergic (hypersensitive) to bevacizumab or any of the other ingredients of this medicine (listed in section 6).
- if you are allergic (hypersensitive) to products from CHO cells (Chinese hamster ovary cells) or recombinant human or humanized antibodies.
- if you are pregnant.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before you use Zirabev.
- if you are allergic (hypersensitive) to bevacizumab or any of the other ingredients of this medicine (listed in section 6).
- if you are allergic (hypersensitive) to products from CHO cells (Chinese hamster ovary cells) or recombinant human or humanized antibodies.
- if you are pregnant.
- Your doctor should write down the drug’s product name and batch number.
- Zirabev may increase the risk of developing holes in the intestinal wall. If you have diseases that cause inflammation inside the abdomen (e.g. diverticulitis, peptic ulcer, colon inflammation associated with chemotherapy treatment), you should tell your doctor about it.
- Zirabev may increase the risk of developing an abnormal connection or passage between two organs or blood vessels (such a connection is called a fistula ). The risk of developing connections between the vagina and any part of the bowel 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 surgery, if you have had a major operation within the last 28 days or if you still have unhealed surgical wounds, you should not use this medicine.
- Zirabev can increase the risk of developing a serious infection in the skin or underlying layers of the skin, especially if you have had a hole in the intestinal wall or problems with wound healing.
- Zirabev may increase the incidence of high blood pressure. If you suffer from high blood pressure that is not well controlled by blood pressure medicine, talk to your doctor as it is important to ensure that your blood pressure is under control before starting treatment with Zirabev.
- If you or have had an aneurysm (enlargement and weakening of a vessel wall) or a rupture in a vessel wall.
- This medicine increases the risk of getting protein in the urine, especially if you already suffer from high blood pressure.
- The risk of getting blood clots in your arteries (a type of blood vessel) may increase if you are over 65, if you have diabetes, or if you have previously had blood clots in your arteries. Talk to your doctor because 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 can cause bleeding, especially tumor-related bleeding. Talk to your doctor if you or your family seem to be suffering from bleeding problems or if for any reason you are using medicines to thin your blood.
- Zirabev may cause bleeding in and around your brain. Discuss this with your doctor if you have a spreading of cancer affecting your brain.
- Zirabev may increase the risk of bleeding in your lungs, including coughing and spitting up blood. Talk to your doctor if you have noticed this in the past.
- Zirabev may increase the risk of developing a weak heart. Your doctor must know if you have ever received anthracyclines (eg doxorubicin, a special type of chemotherapy used to treat certain cancers) or had radiation therapy to the chest, or if you have heart disease.
- This medicine can cause infection and a decrease in the number of neutrophils (a type of blood cell important for your protection against bacteria).
- It is possible that Zirabev can cause hypersensitivity and/or infusion reactions (reactions related to your injection of this medicine). Tell your doctor, pharmacist, or nurse if you have had problems in the past after injection, such as dizziness/fainting, shortness of breath, swelling, or rash.
- A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with Zirabev treatment. If you have headaches, vision changes, confusion, or seizures with or without high blood pressure, contact your doctor.
Contact your doctor even if these statements above only applied to you earlier in your life. Before you receive Zirabev or while you are being treated with Zirabev:
- if you have or have had pain in your mouth, teeth, and/or jaw, swelling or tenderness inside your mouth, numbness or a feeling of heaviness in your jaw, or if a tooth becomes loose, talk to your doctor and dentist immediately.
- if you need dental treatment or dental surgery, tell your dentist that you are being treated with Zirabev, especially if you are also receiving or have received intravenous bisphosphonates.
You may be advised to have your teeth examined before starting treatment with Zirabev.
Children and young people
Use of Zirabev in children and adolescents under 18 years of age is not recommended as safety and benefit have not been established in these patient groups.
Bone tissue death ( osteonecrosis ) in bones other than the jaw has 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 take any other medicines.
Combining Zirabev with another medicine called sunitinib malate (prescribed for kidney and gastrointestinal cancer) can cause serious side effects. Talk to your doctor to make sure you don’t combine these medications.
Tell your doctor if you are using platinum- or taxane-based therapy for lung or disseminated breast cancer. These treatments in combination with Zirabev may increase the risk of serious side effects.
Inform your doctor if you have recently received, or are receiving, radiation treatment.
Pregnancy, breastfeeding, and fertility
You must not use Zirabev if you are pregnant. Zirabev can harm your unborn baby because it can prevent the formation of new blood vessels. Your doctor should 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 shortly.
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 the growth and development of your child.
Zirabev can impair female fertility. Contact your doctor for more information. Consult a doctor, pharmacist, or nurse before taking any medicine.
Driving ability and use of machinery
Bevacizumab has not been shown to reduce your ability to drive or use tools or machines. However, drowsiness and fainting have been reported with the use of bevacizumab. If you experience symptoms that affect your vision, concentration, or ability to react, do not drive or operate machinery until the symptoms have disappeared.
Zirabev contains sodium
This medicine contains 3.0 mg of sodium (the main ingredient in common/table salt) per 4 ml vial. This corresponds to 0.15% of the maximum recommended daily intake of sodium for adults.
This medicine contains 12.1 mg of sodium (the main ingredient in common/table salt) per 16 ml vial. This corresponds to 0.61% of the maximum recommended daily intake of sodium for adults.
Depending on your body weight and dosage of Zirabev, you may need to receive several vials. This should be taken into account if you have been prescribed a low-salt diet.
How to use Zirabev
Dosage and dosage frequency
The 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 kg of your body weight. Your doctor will prescribe the Zirabev dose that is right for you. You will be treated with Zirabev once every two or three weeks. The number of infusions you receive depends on how you respond to treatment; you should continue to use this medicine until Zirabev can no longer prevent your tumor from growing. Your doctor will discuss this with you.
Mode of administration
Do not shake the vial. Zirabev is a concentrate for infusion solution. Depending on the dose prescribed by the doctor, some or all of the contents of the Zirabev vial will be diluted with sodium chloride (common salt) solution before use. A doctor or nurse will give you the diluted Zirabev solution as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If you tolerate this well, the second infusion will be given over 60 minutes. Later infusions can be given over 30 minutes.
Treatment with Zirabev should be temporarily discontinued
- if you develop severe high blood pressure that requires treatment with blood pressure medicine,
- if you have problems with wound healing after surgery,
- if you have surgery.
Treatment with Zirabev should be stopped completely if you develop
- severe high blood pressure that cannot be controlled with blood pressure medication; or a sudden increase in blood pressure,
- protein in the urine and swelling in the body at the same time,
- a hole in your intestinal wall,
- an abnormal tube-like connection or passage between the trachea and the esophagus, between internal organs and the skin, between the vagina and any part of the intestine, or between other tissues that should not normally be connected ( fistula ), and which is judged by your doctor to be serious,
- serious infection in the skin or underlying layers of the skin,
- a blood clot in your arteries,
- a blood clot in the blood vessels of the lungs,
- any heavy bleeding.
If you get more Zirabev than you should
- You can develop severe migraines. If this happens, talk to your doctor, pharmacist, or nurse immediately.
If a Zirabev dose is missed
- Your doctor will decide when you should receive your next dose of Zirabev. You should discuss this with your doctor.
If you stop using Zirabev
Ending your treatment with Zirabev may stop the effect on your tumor growth. Do not stop treatment with Zirabev unless you have discussed this with your doctor.
If you have further questions about this medicine, contact your doctor, pharmacist, or nurse
Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get side effects, talk to your doctor, pharmacist, or nurse. This also applies to any side effects that are not mentioned in this information.
The side effects listed below were seen when bevacizumab was given together with chemotherapy. This does not necessarily mean that these side effects were caused by bevacizumab.
Allergic reactions
If you have an allergic reaction, tell your doctor or healthcare professional right away. These signs may include difficulty breathing or chest pain. You may also experience reddening of the skin or a rash, chills and shaking, nausea, or vomiting.
You must seek help immediately if you experience any of the side effects mentioned below.
Serious side effects, which may be very common (may affect more than 1 in 10 users), include:
- high blood pressure,
- feeling of numbness or tingling in the hands or feet,
- reduced number of blood cells in the blood, including white blood cells that help protect against infection (this may occur along with fever), and platelets that help the blood to clot,
- the feeling of weakness and lack of energy
- fatigue,
- diarrhea, nausea, vomiting, and abdominal pain.
Serious side effects, which may be common (may affect up to 1 in 10 users), include:
- hole in the gut,
- bleeding, including bleeding in the lungs in patients with non-small cell lung cancer,
- blockage of the arteries with a blood clot,
- blockage of the veins with a blood clot,
- blockage of the blood vessels in the lungs by a blood clot,
- blockage of the veins in the legs with a blood clot,
- heart failure,
- problems with wound healing after surgery,
- redness, peeling of the skin, tenderness, pain, or blisters on fingers or feet,
- reduced number of red blood cells in the blood,
- lack of energy,
- stomach and intestinal problems,
- muscle and joint pain, muscle weakness,
- dry mouth combined with thirst and/or decreased or dark-colored urine,
- inflammation of the mucous membrane of the mouth and stomach, lungs and airways, reproductive organs and urinary tract,
- ulcers in the mouth and esophagus, which can be painful and cause difficulty swallowing,
- pain, including headache, back pain, and pain in the pelvis and anal region,
- localized war formation,
- infection, and especially infection of the blood or bladder,
- reduced blood supply to the brain, or stroke (blood clot in the brain or cerebral hemorrhage),
- somnolence,
- nosebleed,
- increase in heart rate ( pulse en),
- the blocked gastrointestinal tract,
- abnormal urine samples ( protein in the urine),
- shortness of breath or low blood oxygen levels,
- skin infections or infections in the deeper layers of the skin,
- fistula: an abnormal tube-like connection between internal organs and skin or other tissues that are not normally connected, including connections between the vagina and the intestine in patients with cervical cancer.
Serious side effects with an unknown frequency (cannot be estimated from the available data) include:
- serious infection in the skin or underlying layers of the skin, especially if you have had a hole in the abdominal wall or problems with wound healing,
- allergic reactions (signs may include difficulty breathing, facial flushing, rash, low or high blood pressure, low oxygen in your blood, chest pain, or nausea/vomiting),
- a negative effect on women’s ability to have children (see the section below after the list of side effects for further recommendations),
- a condition of the brain with symptoms including convulsions (seizures), headache, confusion, and vision changes (posterior reversible encephalopathy syndrome or PRES),
- signs indicating changes in normal brain function (headache, vision changes, confusion, or seizures) and high blood pressure,
- an enlargement and weakening of a vessel wall or a rupture in a vessel wall ( aneurysms and arterial dissections),
- blood clots in very small blood vessels in the kidney,
- abnormally high blood pressure in the blood vessels in the lungs, which causes the right side of the heart to work harder than normal,
- a hole in the septum (the cartilage wall that separates the nostrils) in the nose,
- a hole in the stomach or intestines,
- an open wound or hole in the lining of the stomach or small intestine (signs may include stomach pain, feeling bloated, black tarry stools or blood in the stool or vomiting blood),
- bleeding from the lower part of the colon,
- ulcers in the gums with an exposed jawbone that do not heal and may be associated with pain and inflammation in the surrounding tissue (see the section below after the list of side effects for further recommendations),
- hole in the gallbladder (symptoms and signs may include stomach pain, fever, and nausea/vomiting).
You must seek help as soon as possible if you experience any of the side effects below.
Very common (may affect more than 1 in 10 users) side effects that were not serious include:
- constipation,
- loss of appetite,
- fever,
- eye problems (including increased tear flow),
- speech disorders,
- change in sense of taste,
- Runny nose,
- dry skin, peeling and inflammation of the skin, change in skin color,
- weight loss,
- nosebleed.
Common (may affect up to 1 in 10 users) side effects that were not serious include:
- voice change and hoarseness.
Patients older than 65 years have an increased risk of suffering from the following side effects:
- blood clots in the arteries which can lead to stroke (blood clot or brain hemorrhage) or heart attack,
- a decrease in the number of white blood cells in the blood and a decrease in the number of platelets that help the blood clot,
- diarrhea,
- malaise,
- headache,
- fatigue,
- high blood pressure.
Zirabev can also cause changes in laboratory tests performed by your doctor. These include decreased numbers of white blood cells, especially neutrophils (a type of white blood cell that helps protect against infection ) in the blood, protein in the urine, decreased blood 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 check how your kidneys are working), decreased hemoglobin (found in red blood cells and which transports oxygen), which can be serious.
Pain in the mouth, teeth, and/or jaw, swelling or tenderness inside the mouth, numbness or a feeling of heaviness in the jaw, or if a tooth becomes loose. These may be signs and symptoms of damage to the jawbone ( osteonecrosis ). Tell your doctor and dentist immediately if you experience any of them.
Fertile women (women who have a regular menstrual cycle) may notice that periods become irregular or absent and may notice decreased 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 blood. It has not been developed or manufactured for injection into the eye. It is therefore not approved to be used in this way. When Zirabev is injected directly into the eye (not approved use), the following side effects may occur:
- Infection or inflammation of the eyeball,
- Redness in the eye, small particles or dots/spots in the field of vision, eye pain,
- Seeing flashes of light in connection with dots/spots which turns into a certain loss of vision,
- Increased pressure in the eye,
- Bleeding in the eye.
How to store Zirabev
Keep this medicine out of the sight and reach of children.
Use before the expiry date which is stated on the outer carton and the vial label after the abbreviation EXP. The expiration date is the last day of the specified month.
Store in a refrigerator (2° C – 8° C). Do not freeze.
Store the vial in the outer carton. Light sensitive.
Infusion solutions should be used immediately after dilution. If not used immediately, the responsibility for shelf life and storage, before and underuse, rests with the user. This storage should normally not be longer than 24 hours at 2º C to 8º C unless the solution has been prepared in a sterile environment. When reconstitution has taken place in a sterile environment, Zirabev is stable for up to 35 days at 2º C to 8º C and for up to 48 hours at temperatures up to 30º C.
Do not use Zirabev if you see particles or discoloration before administration.
Medicines must not be thrown into the drain or among the household waste. Ask the pharmacist how to dispose of medicines that are no longer used.
These measures will help to protect the environment.
Contents of the packaging and other information
Contents declaration
- The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumabEach 4 ml vial contains 100 mg of bevacizumabEach 16 ml vial contains 400 mg of bevacizumab
- Other ingredients are sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide (for pH adjustment), and water for injections (see section 2 “Zirabev contains sodium”).
Appearance and package sizes of the medicine
Zirabev is a concentrate for infusion liquid, solution. The concentrate is a clear to slightly opalescent, colorless to slightly brown liquid in a glass vial with a rubber stopper. Each vial contains 100 mg bevacizumab in a 4 ml solution or 400 mg bevacizumab in a 16 ml solution. Each pack of Zirabev contains one vial.
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Manufacturer
Pfizer Ireland Pharmaceuticals, Grange Castle Business Park, Clondalkin, Dublin 22, Ireland
Or
Pfizer Service Company BV, Hoge Wei 10, Zaventem, 1930, Belgium
For further information about this medicinal product, contact the representative of the marketing authorization holder:
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