Zirabev

Patient Information Leaflet

Zirabev 25 mg/ml concentrate for solution for infusion

bevacizumab
Please 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 questions, ask your doctor, pharmacist or nurse.
If you get any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.
Contents of this leaflet:

1. What Zirabev is and what it is used for
2. What you need to know before you use 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 present on the lining of blood and lymphatic vessels in the body. The VEGF protein promotes
the growth of blood vessels within the tumour; these blood vessels supply the tumour with nutrients and
oxygen. Once bevacizumab binds to VEGF, tumour growth is inhibited by blocking the development of
blood vessels that supply nutrients and oxygen to the tumour.

Zirabev is a medicine used to treat adult patients with advanced colorectal cancer, i.e. cancer of the
colon or rectum. Zirabev will be administered in combination with a fluoropyrimidine-based
chemotherapy regimen.

Zirabev is also used to treat adult patients with metastatic breast cancer. In patients with this type of
cancer, Zirabev will be administered in combination with a chemotherapy regimen based on paclitaxel or
capecitabine.

Zirabev is also used to treat adult patients with advanced non-small cell lung cancer. Zirabev will be
administered together with a platinum-based chemotherapy regimen.

Zirabev is also used to treat adult patients with advanced non-small cell lung cancer when tumour cells
have specific mutations in a protein called epidermal growth factor receptor (EGFR). Zirabev will be
administered in combination with erlotinib.

Zirabev is furthermore used to treat adult patients with advanced renal cell carcinoma. In patients with
this type of cancer, Zirabev will be administered in combination with another type of medicine called
interferon.

Zirabev is also used to treat adult women with advanced epithelial ovarian cancer, fallopian tube
carcinoma, or primary peritoneal carcinoma. In patients with these types of cancer, Zirabev will be
administered in combination with carboplatin and paclitaxel.

Zirabev will be administered in combination with carboplatin and gemcitabine or with carboplatin and
paclitaxel when used in adult women with advanced epithelial ovarian cancer, fallopian tube carcinoma,
or primary peritoneal carcinoma whose disease has recurred at least 6 months after the last time they
were treated with a platinum-based chemotherapy regimen.

Zirabev will be administered in combination with paclitaxel, topotecan, or pegylated liposomal
doxorubicin when used in adult women with advanced epithelial ovarian cancer, fallopian tube
carcinoma, or primary peritoneal carcinoma whose disease has recurred within 6 months of the last
time they were treated with a platinum-based chemotherapy regimen.

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

2. What you need to know before using Zirabev

Do not use Zirabev

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

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Zirabev

• Your doctor must 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 conditions causing abdominal inflammation (e.g. diverticulitis, gastric ulcers, chemotherapy-associated colitis), discuss this with your doctor.
• Zirabev may increase the risk of developing an abnormal connection or passage between two organs or blood vessels. The presence of persistent, recurrent, or metastatic cervical carcinoma may increase the risk of developing connections between the vagina and any part of the gastrointestinal tract.
• This medicine may increase the risk of bleeding or cause problems with wound healing after surgery. Do not take this medicine if you are scheduled for surgery, if you have undergone major surgery within the last 28 days, or if you have a surgical wound that has not yet healed.
• Zirabev may increase the risk of developing severe skin infections or infections in deeper layers beneath the skin, especially if you have intestinal wall perforations or problems with wound healing.
• Zirabev may increase the incidence of high blood pressure. If you have uncontrolled high blood pressure despite antihypertensive medication, discuss this with your doctor. It is important to ensure your blood pressure is under control before starting treatment with Zirabev.
• If you have or have had an aneurysm (dilation and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.
• This medicine increases the risk of having protein in the urine, especially if you already have high blood pressure.
• The risk of developing blood clots in arteries (a type of blood vessel) may increase if you are over 65 years old, have diabetes, or have a history of arterial blood clots. Talk to your doctor, as blood clots can lead to heart attacks and strokes.
• Zirabev may also increase the risk of developing blood clots in veins (a type of blood vessel).
• This medicine can cause bleeding, particularly tumor-related bleeding. Consult your doctor if you or members of your family tend to have bleeding problems or if you are taking blood-thinning medications for any reason.
• Zirabev may cause bleeding within or around the brain. Consult your doctor if you have metastatic brain tumors.
• Zirabev may increase the risk of bleeding in the lungs, including coughing up blood or blood in saliva. Discuss with your doctor if you have experienced these events previously.
• Zirabev may increase the risk of developing heart failure. It is important that your doctor knows if you have previously received therapy with anthracyclines (e.g. doxorubicin, a specific type of chemotherapy used to treat certain cancers) or thoracic radiotherapy, or if you have heart disease.
• This medicine may cause infections and a reduction in neutrophil count (a type of blood cell important for protection against bacteria).
• Zirabev may cause hypersensitivity (including anaphylactic shock) and/or infusion reactions (reactions related to the injection of the medicine). Inform your doctor, pharmacist, or nurse if you have previously experienced problems after injections, such as dizziness/fainting, shortness of breath, swelling, or rashes.
• A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with bevacizumab treatment. If you experience headache, visual disturbances, confusion, or seizures with or without elevated blood pressure, contact your doctor immediately.

Talk to your doctor even if any of the above conditions occurred only in the past.
Before starting or during treatment with Zirabev:

• if you have had or currently have pain in the mouth, teeth, and/or jaw, or swelling or inflammation in the mouth, or numbness or a feeling of heaviness in the jaw, or if you lose a tooth, inform your doctor and dentist immediately;
• if you need invasive dental treatment or dental surgery, inform your dentist that you are being treated with Zirabev, especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting
treatment with Zirabev.
Children and adolescents
Zirabev therapy is not recommended in children and adolescents under 18 years of age
because neither safety nor benefit has been established in this patient population.
Bone tissue death (osteonecrosis) in bones other than the jaw has been observed in
patients under 18 years of age treated with bevacizumab.
Other medicines and Zirabev
Inform 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 tumors) may cause serious side effects. Discuss with your doctor to ensure these medicines are not used together.
Inform your doctor if you are receiving platinum-based or taxane therapies for metastatic lung or breast cancer. These therapies 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
Do not use this medicine if you are pregnant. Zirabev may harm the unborn child, as it can interfere with the formation of new blood vessels. Your doctor will advise you to use adequate contraception during treatment with Zirabev
and for at least 6 months after the last dose of Zirabev.
If you are pregnant, suspect you are pregnant during treatment with this
medicine, or are planning a pregnancy in the near future, speak to your
doctor immediately.
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 the infant.
Zirabev may reduce female fertility. Consult your doctor for further information.
Ask your doctor, pharmacist, or nurse for advice before taking any
medicine.
Driving and using machines
Bevacizumab has not been shown to reduce the 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 or concentration, or your ability to react, do not drive or operate machinery until symptoms resolve.
Zirabev contains sodium and polysorbate 80
Sodium
This medicine contains 3.0 mg of sodium (a main component of table salt) in each 4 ml vial. This corresponds to 0.15% of the maximum daily recommended dietary intake for an adult.
This medicine contains 12.1 mg of sodium (a main component of table salt) in each 16 ml vial. This corresponds to 0.61% of the maximum daily recommended dietary intake for an adult.
Depending on your body weight and the dose of Zirabev required, 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 per 100 mg/4 ml vial and 3.2 mg per 400 mg/16 ml vial, equivalent to 0.2 mg/ml. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use Zirabev

Dose and frequency of administration
The dose of Zirabev required depends on your body weight and the type of tumour to be treated.
The recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of body weight. Your doctor will prescribe Zirabev at the appropriate dose for you. Treatment with Zirabev will be administered once every 2 or 3 weeks. The number of infusions you will receive depends on your response to treatment; however, you should continue receiving this treatment until Zirabev is no longer able to block the growth of your tumour. 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. Your 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 this is well tolerated, the second infusion may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Zirabev administration must be temporarily interrupted if

• severe high blood pressure occurs, requiring treatment with medicines to control blood pressure;
• you experience problems with wound healing after surgery;
• you are scheduled to undergo a surgical procedure.

Zirabev administration must be permanently discontinued if any of the following occurs

• severe high blood pressure that cannot be controlled with antihypertensive medicines, or sudden and severe increase in blood pressure;
• presence of protein in the urine associated with oedema (swelling of the body);
• perforation of the intestinal wall;
• an abnormal connection or passage between the trachea and oesophagus, internal organs and skin, vagina and any part of the gastrointestinal tract, or between other tissues not normally connected (fistula), as judged by the doctor to be severe;
• severe skin infections or infections of deeper layers beneath the skin;
• blood clots in the arteries;
• blood clots in the pulmonary blood vessels;
• severe bleeding of any type.

If too much Zirabev is administered

• you may experience a severe headache. In this case, contact your doctor, pharmacist or nurse immediately.

If you forget to receive a dose of Zirabev

• Your doctor will decide the most appropriate time for you to receive the next dose of Zirabev. Discuss this with your doctor.

If you stop treatment with Zirabev
Stopping treatment with Zirabev may cause the inhibition of tumour growth to cease. Do not stop treatment with Zirabev without first discussing it with your doctor.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any side effect, including those not listed in this leaflet, please tell your doctor, pharmacist or nurse.
The side effects listed below have been observed in patients treated with bevacizumab in combination with chemotherapy. This does not mean that these side effects were necessarily caused by bevacizumab.

Allergic reactions
If you have an allergic reaction, tell your doctor or a healthcare professional immediately. Signs may include: difficulty breathing or chest pain. You may also experience skin redness, flushing or rash, chills and shivering, feeling unwell (nausea) or vomiting, swelling, dizziness, rapid heartbeat and loss of consciousness.

If you experience any of the side effects described below, seek immediate help.

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

• high blood pressure;
• numbness or tingling in the hands or feet;
• reduced number of blood cells, including white blood cells (which fight infections – this may be accompanied by fever) and cells involved in blood clotting;
• feeling weak and lacking energy;
• tiredness;
• diarrhoea, nausea, vomiting and abdominal pain.

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

• intestinal perforation;
• bleeding, including bleeding into the lungs in patients with non-small cell lung cancer;
• blocked arteries due to blood clots;
• blocked veins due to blood clots;
• blocked pulmonary blood vessels due to blood clots;
• blocked leg veins due to blood clots;
• heart failure;
• problems with wound healing after surgery;
• redness, peeling, soreness, pain or blistering on the fingers or toes;
• reduced number of red blood cells;
• lack of energy;
• stomach and intestinal disorders;
• muscle and joint pain, muscle weakness;
• dry mouth associated with thirst and/or reduced or dark urine;
• inflammation of the lining of the mouth, intestine, lungs and airways, reproductive and urinary tract;
• mouth and oesophageal ulcers that may cause pain and difficulty swallowing;
• pain, including headache, back pain and pain in the pelvic area and around the anus;
• localized abscesses;
• infection, particularly blood or bladder infection;
• reduced blood supply to the brain or stroke;
• drowsiness;
• nosebleeds;
• increased heart rate (pulsations);
• intestinal blockage;
• changes in urine tests (presence of protein in urine);
• shortness of breath or reduced oxygen levels in the blood;
• skin infections or infections of deeper skin layers;
• fistulas: abnormal tubular connections between internal organs and skin or other tissues that are not normally connected, including connections between the vagina and gastrointestinal tract in patients with cervical cancer;
• allergic reactions (signs may include difficulty breathing, facial redness, rash, low or high blood pressure, low oxygen levels in the blood, chest pain, or nausea/vomiting).

Serious side effects that are rare (may affect up to 1 in 1,000 people) include:

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

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

• severe skin infections or infections in deeper layers under the skin, especially if you have had perforations in the intestinal wall or problems with wound healing;
• a negative effect on women’s ability to have children (see the paragraphs following the list of side effects for further recommendations);
• a brain condition with symptoms such as seizures, headache, confusion and vision changes (posterior reversible encephalopathy syndrome (PRES));
• symptoms suggesting changes in normal brain function (headache, visual disturbances, confusion or seizures) and high blood pressure;
• dilation and weakening of the wall of a blood vessel or a tear in the blood vessel wall (aneurysms and arterial dissections);
• blockage of small blood vessel(s) in the kidney;
• abnormally high blood pressure in the blood vessels of the lungs, making the right side of the heart work harder than normal;
• perforation of the cartilage wall separating the nostrils;
• perforation of the stomach or intestine;
• an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, feeling of bloating, black tarry stools, blood in the stool or blood in vomit);
• bleeding from the lower part of the large intestine;
• gum lesions, with exposure of jawbone that does not heal, possibly associated with pain and inflammation of surrounding tissue (see the paragraphs following the list of side effects for further recommendations);
• gallbladder perforation (symptoms and signs may include abdominal pain, fever and nausea/vomiting).

If you experience any of the side effects described below, seek help as soon as possible.

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

• constipation;
• loss of appetite;
• fever;
• eye problems (including increased tearing);
• changes in speech;
• altered sense of taste;
• runny nose;
• dry, peeling and inflamed skin, changes in skin colour;
• weight loss;
• nosebleeds.

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

• changes in voice and hoarseness.

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

• blood clots in arteries, which may lead to stroke or heart attack;
• reduced number of white blood cells and cells involved in blood clotting;
• diarrhoea;
• feeling unwell;
• headache;
• feeling fatigued;
• high blood pressure.

Zirabev may also cause changes in laboratory test results ordered by your doctor. These include: reduced number of white blood cells, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in urine, reduced levels of potassium, sodium or phosphorus (a mineral) in the blood, increased blood glucose, increased alkaline phosphatase (an enzyme) in the blood; increased serum creatinine (a protein measured in blood tests to assess kidney function); reduced haemoglobin (found in red blood cells and responsible for oxygen transport), which may be severe.

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

Women of premenopausal age (women who have menstrual cycles) may notice irregularities in their menstrual cycles, absence of menstruation, and may experience negative effects on fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.

Zirabev has been developed and manufactured for the treatment of cancer by intravenous injection. It has not been developed or manufactured for administration by injection into the eye. Therefore, this route of administration is not authorised. When Zirabev is injected directly into the eye (unapproved use), the following side effects may occur:

• infection or inflammation of the eyeball;
• eye redness, appearance of particles or floating spots in the visual field (“floaters”), eye pain;
• flashes of light and “floaters” progressing to partial loss of visual field;
• increased eye pressure;
• eye haemorrhages.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please tell your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zirabev

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the outer packaging and
on the label of the vial after the abbreviation “Exp.”. The expiry date refers to the last
day of that month.
Store in a refrigerator (2 °C - 8 °C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Diluted infusion solutions should be used immediately. If not used immediately, storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at a temperature between 2 °C-8 °C, unless the infusion solutions have been prepared under sterile conditions.
When dilution has been carried out under sterile conditions, Zirabev is stable for up to 35 days at a temperature between 2 °C-8 °C after dilution, and for up to 48 hours at temperatures not exceeding 30 °C.
Do not use Zirabev if you notice particulate matter or changes in colour before administration.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Zirabev contains

• 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”).

Description of the appearance of Zirabev and contents of the pack
Zirabev is a concentrate for solution for infusion. The concentrate is a clear to slightly opalescent, colourless to light brown liquid in a glass vial closed 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 Zirabev pack contains one vial.
Marketing Authorisation Holder
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium
Manufacturer
Pfizer Service Company BV, Hermeslaan 11, 1932 Zaventem, Belgium
For further information about this medicine, contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Κύπρος
Luxembourg/Luxemburg Pfizer Eλλάς A.E. (Cyprus Branch)
Pfizer NV/SA T \η\λ : +357 22817690
Tél/Tel: +32 (0)2 554 62 11
Česká republika Magyarország
Pfizer, spol. s r.o. Pfizer Kft.
Tel: +420 283 004 111 Tel.: + 36 1 488 37 00
Danmark Malta
Pfizer ApS Drugsales Ltd
Tlf.: +45 44 20 11 00 Tel: +356 21419070/1/2
Deutschland Nederland
PFIZER PHARMA GmbH Pfizer bv
Tel: +49 (0)30 550055-51000 Tel: +31 (0)800 63 34 636
България Norge
Пфайзер Люксембург САРЛ, Pfizer AS
Клон България Tlf: +47 67 52 61 00
Teл.: +359 2 970 4333
Eesti Österreich
Pfizer Luxembourg SARL Eesti filiaal Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 666 7500 Tel: +43 (0)1 521 15-0
Ελλάδα Polska
Pfizer Eλλάς A.E. Pfizer Polska Sp. z o.o.
Τηλ: +30 210 6785800 Tel.: +48 22 335 61 00
España Portugal
Pfizer, S.L. Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00 Tel: +351 21 423 5500
France România
Pfizer Pfizer Romania S.R.L
Tél: +33 (0)1 58 07 34 40 Tel: +40 (0) 21 207 28 00
Hrvatska Slovenija
Pfizer Croatia d.o.o. Pfizer Luxembourg SARL
Tel: +385 1 3908 777 Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: +386 (0)1 52 11 400
Ireland Slovenská republika
Pfizer Healthcare Ireland Unlimited Pfizer Luxembourg SARL, organizačná zložka
Company Tel: + 421 2 3355 5500
Tel: 1800 633 363 (toll free)
Tel: +44 (0)1304 616161
Ísland Suomi/Finland
Icepharma hf. Pfizer Oy
Sími: +354 540 8000 Puh/Tel: +358 (0)9 430 040
Italia Sverige
Pfizer S.r.l. Pfizer AB
Tel: +39 06 33 18 21 Tel: +46 (0)8 550 520 00
Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: + 371 670 35 775
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel: +370 5 251 4000

Other sources of information
More detailed information on this medicine is available on the website of the European Medicines Agency: https://www.ema.europa.eu .
ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION OF THE TERMS OF THE MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for bevacizumab, the scientific conclusions of the PRAC are as follows:
In view of the available data on hyaline glomerular occlusive microangiopathy reported in the literature, including in some cases a positive de-challenge, and in view of a plausible mechanism of action, the PRAC considers that a causal relationship between bevacizumab and hyaline glomerular occlusive microangiopathy is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing bevacizumab should therefore be amended accordingly.
Having reviewed the PRAC's recommendation, the Committee for Medicinal Products for Human Use (CHMP) agrees with the general conclusions and the reasoning of the recommendation.
Grounds for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions on bevacizumab, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing bevacizumab remains favourable, subject to the proposed changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).