Package leaflet: Information for the user

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

1. What Oyavas is and what it is used for

Oyavas 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 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 tumors; these blood vessels supply the tumor with nutrients
and oxygen. Once bevacizumab binds to VEGF, tumor growth is inhibited by blocking the development
of blood vessels that supply nutrients and oxygen to the tumor.

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

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

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

Oyavas 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). Oyavas will
be administered in combination with erlotinib.

Oyavas is also used to treat adult patients with advanced renal cell (kidney) cancer. In patients with this
type of tumor, Oyavas will be administered in combination with another medicine called interferon.

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

When used in adult female patients 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, Oyavas will be administered in combination with carboplatin
and gemcitabine or with carboplatin and paclitaxel.

When used in adult female patients 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, Oyavas will be administered in combination with paclitaxel,
topotecan, or pegylated liposomal doxorubicin.

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

2. What you should know before using Oyavas

Do not use Oyavas:

if you are allergic to bevacizumab or to 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 using Oyavas:

Oyavas may increase the risk of developing intestinal wall perforations. If you have conditions causing abdominal inflammation (e.g., diverticulitis, stomach ulcer, chemotherapy-associated colitis), discuss this with your doctor.
Oyavas may increase the risk of developing abnormal connections or passages between two organs or blood vessels. Persistent, recurrent, or metastatic cervical cancer may increase the risk of developing connections between the vagina and any part of the intestine.
This medicine may increase the risk of bleeding or impair wound healing after surgery. 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, you must not take this medicine.
Oyavas 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 impaired wound healing.
Oyavas may increase the incidence of high blood pressure. If you have uncontrolled high blood pressure despite medication, discuss this with your doctor. It is important to ensure your blood pressure is well-controlled before starting treatment with Oyavas.
If you have or have had an aneurysm (a weakened and dilated blood vessel wall) or a tear in the wall of a blood vessel.
This medicine increases the risk of 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 previously had arterial blood clots. Discuss this with your doctor, as blood clots can lead to heart attacks and strokes.
Oyavas 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 clotting disorders or if you are taking blood-thinning medications for any reason.
Oyavas can cause bleeding in and around the brain. Consult your doctor if you have metastatic cancer affecting the brain.
Oyavas 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 such events in the past.
Oyavas may increase the risk of developing heart failure. It is important that your doctor knows if you have previously received treatment 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).
Oyavas 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 Oyavas treatment. If you experience headache, visual disturbances, confusion, or seizures with or without high blood pressure, contact your doctor immediately.
In patients under 18 years of age treated with Oyavas, bone tissue death (osteonecrosis) has been observed in bones other than the jaw. Pain in the mouth, teeth, and/or jaw, swelling or blisters in the mouth, numbness or heaviness in the jaw, or tooth loss may be signs and symptoms of jawbone damage (osteonecrosis). Inform your doctor and dentist immediately if any of these events occur.

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

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 heaviness in the jaw, or if you lose a tooth, report this immediately to your doctor and dentist.
if you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Oyavas, especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting
treatment with Oyavas.
Oyavas has been developed and manufactured for cancer treatment via intravenous injection. It has not
been developed or manufactured for administration by intraocular injection. Therefore, this route of
administration is not authorized. When Oyavas is injected directly into the eye (off-label use), the
following adverse effects may occur:

infection or inflammation of the eyeball,
eye redness, appearance of particles or floating bodies in the visual field ("floaters"), eye pain,
flashes of light with "floaters" progressing to partial vision loss,
increased eye pressure,
eye bleeding.

Children and adolescents
Treatment with Oyavas is not recommended in children and adolescents under 18 years of age
because safety and efficacy have not been established in this patient population.
Other medicines and Oyavas
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other
medicines.
Combining Oyavas with another medicine called sunitinib malate (prescribed for kidney and
gastrointestinal cancer) may cause serious adverse effects. Talk to your doctor to ensure you do not
combine these medicines.
Inform your doctor if you are receiving platinum-based or taxane therapies for metastatic lung or breast
cancer. These therapies in combination with Oyavas 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. Oyavas may harm the unborn baby as it can interfere with
the formation of new blood vessels. Your doctor will advise you to use adequate contraception during
treatment with Oyavas and for at least 6 months after the last dose of Oyavas.
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor or
pharmacist before taking this medicine.
You must not breastfeed during treatment with Oyavas and for at least 6 months after the last dose, as
Oyavas may interfere with the baby's growth and development.
Oyavas may impair female fertility. Consult your doctor for further information.
Premenopausal women (women who have menstrual cycles) may experience menstrual irregularities,
absence of menstruation, and potentially negative effects on fertility. If you are considering having
children, discuss this with your doctor before starting treatment.
Driving and using machines
Oyavas has not been shown to reduce the ability to drive or operate tools or machinery.
However, drowsiness and fainting have been reported with Oyavas use. If you experience symptoms
affecting your vision, concentration, or reaction ability, do not drive or operate machinery until symptoms
resolve.
Oyavas contains sodium and polysorbate 20
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e., it is essentially "sodium-free".
This medicine contains 1.6 mg of polysorbate 20 per 100 mg/4 mL vial and 6.4 mg per 400 mg/16 mL
vial, equivalent to 0.4 mg/mL. Polysorbates may cause allergic reactions. Inform your doctor if you have
known allergies.

3. How to use Oyavas

Dose and frequency of administration
The required dose of Oyavas depends on your body weight and the type of cancer 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 Oyavas at the appropriate dose for you. Treatment with Oyavas 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 Oyavas is no longer able to block the growth of your tumor. Your doctor will discuss this with you.

Method and route of administration
Do not shake the vial. Oyavas is a concentrate for solution for infusion. Depending on the prescribed dose, part or all of the contents of the vial will be diluted with a sodium chloride solution before use. Your doctor or nurse will administer this diluted Oyavas solution as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If the first infusion is well tolerated, the second may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Oyavas administration must be temporarily interrupted

if severe high blood pressure problems occur, requiring treatment with medications to control blood pressure,
if you experience impaired wound healing after surgery,
if you are scheduled to undergo surgery.

Oyavas administration must be permanently discontinued if any of the following occur

severe high blood pressure that cannot be controlled with antihypertensive medications, or sudden and severe increase in blood pressure,
presence of protein in the urine associated with edema (body swelling),
perforation of the intestinal wall,
an abnormal connection or passage between the trachea and esophagus, between internal organs and skin, between the vagina and any part of the intestinal 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 kind.

If you take more Oyavas than you should

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

If a dose of Oyavas is missed

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

If you stop treatment with Oyavas
Stopping treatment with Oyavas may cause the tumor growth control effect to cease. Do not stop treatment with Oyavas 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.
The side effects listed below have been observed in patients treated with Oyavas in combination with chemotherapy. This does not mean that these side effects were necessarily caused by Oyavas.

Allergic reactions
If you experience an allergic reaction, inform 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 sickness (vomiting), swelling, mild confusion, 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 help fight infections—this may be accompanied by fever) and cells involved in blood clotting,
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 pulmonary haemorrhage in patients with non-small cell lung cancer,
blocked arteries due to blood clots,
blocked veins due to blood clots,
pulmonary blood vessels blocked by blood clots,
blocked leg veins due to blood clots,
heart failure,
wound healing problems after surgery,
redness, peeling, tenderness, 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, airways, reproductive organs, and urinary tract,
mouth and oesophageal ulcers that may cause pain and difficulty swallowing,
pain, including headache, back pain, and pain in the pelvic or anal area,
localized abscesses,
infections, particularly blood infection (septicaemia) or bladder infection,
reduced blood flow to the brain or stroke,
drowsiness,
nosebleeds,
increased heart rate (palpitations),
intestinal obstruction,
abnormal urine tests (presence of protein in the 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:

severe and sudden allergic reaction, with difficulty breathing, swelling, mental confusion, 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 of deeper layers beneath the skin, especially if you have had intestinal wall perforations or wound healing problems,
a negative effect on women’s fertility (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 (posterior reversible encephalopathy syndrome or PRES),
symptoms suggesting changes in normal brain function (headache, vision 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 one or more small blood vessels in the kidney,
abnormally high blood pressure in the lung vessels, making the right side of the heart work harder than normal,
perforation of the cartilage wall separating the nostrils,
perforation of the stomach or intestinal wall,
an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, feeling of abdominal 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).

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

Very common side effects (may affect more than 1 in 10 people), which are not serious, include:

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

Common side effects (may affect up to 1 in 10 people), which are not 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 cells and cells involved in blood clotting,
diarrhoea,
feeling unwell,
headache,
fatigue,
high blood pressure.

Oyavas 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 the 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); reduced haemoglobin (found in red blood cells and responsible for oxygen transport), which may be severe.

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

5. How to store Oyavas

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 “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, the storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at a temperature of 2°C–8°C, unless the infusion solutions have been prepared under sterile conditions.
When dilution has been carried out under sterile conditions, Oyavas is stable for up to 30 days at a temperature of 2°C–8°C after dilution and for up to 48 hours at temperatures not exceeding 30°C.
Do not use Oyavas if you notice particulate matter or any change 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. Pack contents and other information

What Oyavas contains

The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab, corresponding to 1.4–16.5 mg/ml when diluted as recommended.
Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.
Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.
The other components are trehalose dihydrate, monobasic monohydrate sodium phosphate, dibasic sodium phosphate, polysorbate 20 (E 432), and water for injections (see section 2 “Oyavas contains sodium and polysorbate 20”).

Description of the appearance of Oyavas and contents of the pack
Oyavas is a concentrate for solution for infusion (sterile concentrate). The concentrate is an opalescent liquid, colourless to yellowish or light brown, in a glass vial closed with a rubber stopper. Each vial contains either 100 mg of bevacizumab in 4 ml of solution or 400 mg of bevacizumab in 16 ml of solution. Each pack of Oyavas contains one vial.

Marketing Authorisation Holder
STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

Manufacturer
GH GENHELIX S.A.
Parque Tecnológico de León
Edificio GENHELIX
C/Julia Morros, s/n
Armunia, 24009 León
Spain
STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

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

België/Belgique/Belgien Lietuva
EG (Eurogenerics) NV UAB „STADA Baltics“
Tél/Tel: +32 24797878 Tel: +370 52603926
България Luxembourg/Luxemburg
STADA Bulgaria EOOD EG (Eurogenerics) NV
Teл.: +359 29624626 Tél/Tel: +32 24797878
Česká republika Magyarország
STADA PHARMA CZ s.r.o. STADA Hungary Kft
Tel: +420 257888111 Tel.: +36 18009747
Danmark Malta
STADA Nordic ApS Pharma.MT Ltd.
Tlf.: +45 44859999 Tel: +356 21337008
Deutschland Nederland
STADAPHARM GmbH Centrafarm B.V.
Tel: +49 61016030 Tel.: +31 765081000
Eesti Norge
UAB „STADA Baltics“ STADA Nordic ApS
Tel: +372 53072153 Tlf: +45 44859999
Ελλάδα Österreich
DEMO S.A. Pharmaceutical Industry STADA Arzneimittel GmbH
Τηλ: +30 2108161802 Tel: +43 136785850
España Polska
Laboratorio STADA, S.L. STADA Pharm Sp. z o.o.
Tel: +34 934738889 Tel: +48 227377920
France Portugal
EG Labo - Laboratoires EuroGenerics Stada, Lda.
Tél: +33 146948686 Tel: +351 211209870
Hrvatska România
STADA d.o.o. STADA M&D SRL
Tel: +385 13764111 Tel: +40 213160640
Ireland Slovenija
Clonmel Healthcare Ltd. Stada d.o.o.
Tel: +353 526177777 Tel: +386 15896710
Ísland Slovenská republika
STADA Arzneimittel AG STADA PHARMA Slovakia, s.r.o.
Sími: +49 61016030 Tel: +421 252621933
Italia Suomi/Finland
EG SpA STADA Nordic ApS, Suomen sivuliike
Tel: +39 028310371 Puh/Tel: +358 207416888
Κύπρος Sverige
STADA Arzneimittel AG STADA Nordic ApS
Τηλ: +49 61016030 Tel: +45 44859999
Latvija
UAB „STADA Baltics“
Tel: +371 28016404

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