Package leaflet: Information for the user

MVASI 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, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

What MVASI is and what it is used for
What you need to know before using MVASI
How to use MVASI
Possible side effects
How to store MVASI
Contents of the pack and other information

1. What MVASI is and what it is used for

MVASI contains the active substance bevacizumab, a humanised monoclonal antibody (a type of protein normally produced by the immune system to help the body defend itself against infection and cancer). Bevacizumab binds selectively to a protein called human vascular endothelial growth factor (VEGF), which is present on the lining of the body's blood and lymphatic vessels. 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.

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

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

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

MVASI is furthermore 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). MVASI will be administered in combination with erlotinib.

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

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

MVASI 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 cancer, or primary peritoneal cancer whose disease has recurred at least 6 months after their last treatment with a platinum-based chemotherapy regimen.

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

MVASI is also used to treat adult women with persistent, recurrent, or metastatic cervical cancer. MVASI 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 MVASI

Do not use MVASI

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 cells (CHO) or to other recombinant human or humanized antibodies.
if you are pregnant.

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

MVASI may increase the risk of developing intestinal wall perforations. If you have conditions causing abdominal inflammation (e.g., diverticulitis, gastric ulcers, chemotherapy-associated colitis), discuss this with your doctor.
MVASI may increase the risk of developing abnormal connections or passages between two organs or vessels. The presence of persistent, recurrent, or metastatic cervical carcinoma may increase the risk of developing connections between the vagina and any section of the gastrointestinal tract.
MVASI may increase the risk of bleeding or complications in 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.
MVASI may increase the risk of developing severe skin infections or infections of deeper layers beneath the skin, especially if you have intestinal wall perforations or problems with wound healing.
MVASI may increase the incidence of high blood pressure. If you have high blood pressure that is not well controlled with antihypertensive medications, discuss this with your doctor. It is important to ensure your blood pressure is under control before starting treatment with MVASI.
MVASI 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.
MVASI may also increase the risk of developing blood clots in veins (a type of blood vessel).
MVASI can cause bleeding, particularly tumor-related bleeding. Consult your doctor if you or members of your family tend to have coagulation disorders or if you are taking medications to thin the blood for any reason.
MVASI may cause bleeding within or around the brain. Consult your doctor if you have metastatic brain tumors.
MVASI may increase the risk of bleeding in the lungs, including blood in cough or saliva. Discuss with your doctor if you have experienced these events in the past.
MVASI 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 tumors) or thoracic radiotherapy, or if you have heart disease.
MVASI may cause infections and a reduction in neutrophil count (a type of blood cell important for protection against bacteria).
MVASI may cause hypersensitivity (including anaphylactic shock) 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 injections, such as dizziness/fainting, shortness of breath, swelling, or skin rashes.
A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with treatment with MVASI. If you experience headache, visual disturbances, confusion, or seizures with or without elevated blood pressure, contact your doctor.
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.

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

if you have had or currently have mouth, tooth, and/or jaw pain, swelling or inflammation in the mouth, numbness or heaviness in the jaw, or lose a tooth, inform your doctor and dentist immediately.
if you need to undergo invasive dental procedures or dental surgery, inform your dentist that you are being treated with MVASI (bevacizumab), especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting treatment with MVASI.
Children and adolescents
Treatment with MVASI is not recommended in children and adolescents under 18 years of age, as neither safety nor efficacy 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 MVASI
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
Combining MVASI with another medicine called sunitinib malate (prescribed for kidney and gastrointestinal tumors) may cause severe adverse 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 MVASI 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 MVASI if you are pregnant. MVASI 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 MVASI and for at least 6 months after the last dose of MVASI.
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 MVASI and for at least 6 months after the last dose of MVASI, as MVASI may interfere with the growth and development of the infant.
MVASI 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
MVASI has not been shown to impair the ability to drive vehicles or operate tools or machinery.
However, drowsiness and fainting have been reported with the use of MVASI. If you experience symptoms affecting your vision or concentration, or your ability to react, do not drive or operate machinery until symptoms resolve.
MVASI contains sodium
MVASI 25 mg/mL concentrate for solution for infusion (4 mL)
This medicine contains 5.4 mg of sodium (the main component of table salt) per 4 mL vial. This corresponds to 0.3% of the maximum daily recommended dietary intake for an adult.
MVASI 25 mg/mL concentrate for solution for infusion (16 mL)
This medicine contains 21.7 mg of sodium (the main component of table salt) per 16 mL vial. This corresponds to 1.1% of the maximum daily recommended dietary intake for an adult.

3. How to use MVASI

Dose and frequency of administration
The dose of MVASI 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 MVASI at the appropriate dose for you. Treatment with MVASI will be administered once
every 2 or 3 weeks. The number of infusions you receive will depend on your response to treatment;
however, you should continue receiving this treatment until MVASI is no longer able to block the growth
of your tumour. Your doctor will discuss this with you.

Method and route of administration
Do not shake the vial. MVASI is a concentrate for solution for infusion. Depending on the prescribed dose,
a portion of the vial contents or the entire vial of MVASI will be diluted with sodium chloride solution
before use. Your doctor or nurse will administer this diluted MVASI solution via intravenous infusion (an intravenous drip).
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.

Administration of MVASI must be temporarily interrupted

if severe high blood pressure problems occur requiring treatment with medicines to control blood pressure,
if you have problems with wound healing after surgery,
if you need to undergo a surgical procedure.

Administration of MVASI must be permanently discontinued if any of the following occur

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 section of the gastrointestinal tract, or between other tissues not normally connected (fistula), judged by the doctor as 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 MVASI 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 MVASI

Your doctor will decide the most appropriate time to administer your next dose of MVASI. Discuss this with your doctor.

If you stop treatment with MVASI
Stopping treatment with MVASI may cause the inhibition of tumour growth to cease. Do not stop treatment with MVASI without first discussing it with your doctor.
If you have any doubts about the use of 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 contact your doctor, pharmacist, or nurse.
The side effects listed below have been observed in patients treated with MVASI in combination with chemotherapy. This does not mean that these side effects were necessarily caused by MVASI.

Allergic reactions
If you experience 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 or flushing, 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 medical help.

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

high blood pressure,
tingling or numbness in the hands or feet,
reduction in blood cell counts, including white blood cells (which 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 side effects that may be common (may affect up to 1 in 10 people) include:

intestinal perforation,
bleeding, including lung bleeding 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 palms of the hands or soles of the feet,
reduction in red blood cell count,
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 mucous membranes 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 and anal area,
localized abscesses,
infection, particularly blood infection or bladder infection,
reduced blood flow to the brain or stroke,
drowsiness,
nosebleeds,
increased heart rate (pulsations),
intestinal obstruction,
changes in urine tests (presence of protein in urine),
shortness of breath or low oxygen levels in the blood,
skin infections or infections of deeper skin layers,
fistulas: abnormal tubular connections between internal organs and the skin or other tissues 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 may be 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 available data) include:

severe skin infections or infections of deeper layers beneath the skin, especially if you have had intestinal wall perforations or problems with wound healing,
a negative effect on women's ability to have children (see the sections following the list of side effects for further recommendations),
a brain condition with symptoms such as seizures, headache, confusion, and vision changes (reversible posterior encephalopathy syndrome, PRES),
symptoms suggesting changes in normal brain function (headache, visual disturbances, confusion, or seizures) and high blood pressure,
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, 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 do not heal, possibly associated with pain and inflammation of surrounding tissue (see the sections following the list of side effects for further recommendations),
gallbladder perforation (symptoms and signs may include abdominal pain, fever, and nausea/vomiting),
dilation and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and arterial dissections).

If you experience any of the side effects described below, seek medical help as soon as possible.
Side effects that are very common (may affect more than 1 in 10 people), which are not considered serious, 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,
loss of body weight,
nosebleeds.

Side effects that are common (may affect up to 1 in 10 people), which are not considered serious, include:

voice changes 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,
reduction in white blood cell count and platelets (which help blood to clot),
diarrhoea,
feeling unwell,
headache,
feeling fatigued,
high blood pressure.

MVASI may also cause changes in laboratory test results prescribed by your doctor. These include: reduced white blood cell count, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in urine, reduced 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), and 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.

Premenopausal women (women who have menstrual periods) may experience menstrual irregularities, absence of menstruation, and may have negative effects on fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.

MVASI has been developed and manufactured for cancer treatment via 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 bevacizumab is injected directly into the eye (unapproved use), the following side effects may occur:

infection or inflammation of the eyeball,
eye redness, appearance of floating particles or 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 contact your doctor, pharmacist, or nurse. You can also report side effects directly through 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 MVASI

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 following the abbreviation "Exp./EXP". The expiry date refers to the last day of the 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.
Infusion solutions should be used immediately after dilution. If immediate use is not possible, the user is responsible for the storage duration and conditions, which normally should not exceed 24 hours at a temperature between 2°C and 8°C, unless the infusion solutions have been prepared under sterile conditions. If dilution has been performed under sterile conditions, MVASI is stable for 35 days at a temperature between 2°C and 8°C, plus an additional 48 hours at a temperature not exceeding 30°C.
Do not use MVASI if particulate matter or colour changes are observed before administration.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What MVASI contains

The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab. Each 4 mL vial of concentrate contains 100 mg of bevacizumab, corresponding to 1.4 mg/mL when diluted as recommended. Each 16 mL vial of concentrate contains 400 mg of bevacizumab, corresponding to 16.5 mg/mL when diluted as recommended.
The other components are disodium phosphate, polysorbate 20, trehalose dihydrate, and water for injections (see section 2 – MVASI contains sodium).

Description of the appearance of MVASI and contents of the pack
MVASI is a concentrate for solution for infusion. The concentrate is a clear to slightly opalescent, colourless to slightly yellow 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 pack of MVASI contains one vial.

Marketing Authorisation Holder and Manufacturer
Amgen Technology (Ireland) UC,
Pottery Road,
Dun Laoghaire,
Co. Dublin,
Ireland

Marketing Authorisation Holder
Amgen Technology (Ireland) UC,
Pottery Road,
Dun Laoghaire,
Co. Dublin,
Ireland

Manufacturer
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
Netherlands

Manufacturer
Amgen NV
Telecomlaan 5-7
1831 Diegem
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
s.a. Amgen n.v. Amgen Switzerland AG Vilniaus filialas
Tél/Tel: +32 (0) 2 7752711 Tel: +370 5 219 7474

България Luxembourg/Luxemburg
Амджен България ЕООД s.a. Amgen
Тел: +359 (0) 2 424 7440 Belgique/Belgien
Tél/Tel: +32 (0)2 7752711

Česká republika Magyarország
Amgen s. r. o. Amgen Kft.
Tel: +420 221 773 500 Tel: +36 - 1 35 44 700

Danmark Malta
Amgen, filial af Amgen AB, Sverige Amgen S.r.l.
Tlf: +45 39617500 Italy
Tel: +39 02 6241121

Deutschland Nederland
Amgen GmbH Amgen B.V.
Tel: +49 89 1490960 Tel: +31 (0)76 5732500

Eesti Norge
Amgen Switzerland AG Vilniaus filialas Amgen AB
Tel: + 372 586 09553 Tlf: +47 23308000

Ελλάδα Österreich
Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Amgen GmbH
Τηλ: +30 210 3447000 Tel: +43 (0)1 50 217

España Polska
Amgen S.A. Amgen Biotechnologia Sp.z o.o.
Tel: +34 93 600 18 60 Tel.: +48 22 581 3000

France Portugal
Amgen S.A.S. Amgen Biofarmacêutica, Lda.
Tél: +33 (0)9 69 363 363 Tel: +351 21 4220606

Hrvatska România
Amgen d.o.o. Amgen România SRL
Tel: + 385 (0)1 562 57 20 Tel: +4021 527 3000

Ireland Slovenija
Amgen Ireland Limited AMGEN zdravila d.o.o.
Tel: + 353 1 8527400 Tel: +386 (0)1 585 1767

Ísland Slovenská republika
Vistor hf Amgen Slovakia, s.r.o.
Sími:+354 535 7000 Tel: +421 2 321 114 49

Italia Suomi/Finland
Amgen S.r.l. Amgen AB, sivuliike Suomessa/Amgen AB, filial
Tel: +39 02 6241121 i Finland
Puh/Tel: +358 (0)9 54900500

Kύπρος Sverige
C.A. Papaellinas Ltd Amgen AB
Τηλ: +357 22741 741 Tel: +46 (0)8 6951100

Latvija United Kingdom (Northern Ireland)
Amgen Switzerland AG Rīgas filiāle Amgen Limited
Tel: +371 257 25888 Tel: +44 (0)1223 420305

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu .

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION(S)

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for bevacizumab, the PRAC's scientific conclusions are as follows:
In view of the available data on hyaline glomerular occlusive microangiopathy reported in the literature, including some cases with positive dechallenge, 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 Human Medicinal Products (CHMP) agrees with its general conclusions and the rationale for the recommendation.

Reasons 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 unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation(s).

Mvasi