Oyavas 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Oyavas 25mg/ml concentrate for solution for infusion

bevacizumab

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is a side effect not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Oyavas is and what it is used for

The active substance in Oyavas is bevacizumab, a humanized monoclonal antibody (a type of protein normally produced by the immune system to help the body defend itself against infections and cancer). Bevacizumab binds selectively to a protein called vascular endothelial growth factor (VEGF), which is located on the walls of blood and lymphatic vessels in the body. The VEGF protein promotes the growth of blood vessels into the tumour, supplying it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumour growth by blocking the formation of new blood vessels that provide the nutrients and oxygen the tumour needs.

Oyavas is a medicine used to treat adult patients with advanced colorectal cancer. Oyavas will be given in combination with a chemotherapy regimen containing a fluoropyrimidine medicine.

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

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

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

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

Oyavas is also used to treat adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. When used in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, Oyavas will be given in combination with carboplatin and paclitaxel.

In adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, Oyavas will be given in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.

In adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, Oyavas will be given in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

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

2. What you need to know before using Oyavas

Do not use Oyavas

• if you are allergic (hypersensitive) to bevacizumab or to any of the other components 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 starting treatment with Oyavas

• Oyavas may increase the risk of developing perforations in the intestinal wall. If you have any condition causing inflammation in the abdomen (e.g., diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.

• Oyavas may increase the risk of developing an abnormal connection between two organs or cavities. The risk of developing fistulas between the vagina and any part of the intestine may be increased if you have persistent, recurrent, or metastatic cervical cancer.

• Oyavas may increase the risk of bleeding or problems with surgical wound healing. You must not use this medicine if you are scheduled for surgery, have undergone major surgery within the last 28 days, or have an unhealed surgical wound.

• Oyavas may increase the risk of developing severe skin infections or deep skin tissue infections, especially if you have had intestinal wall perforations or wound healing problems.

• Oyavas may increase the risk of high blood pressure. If you have uncontrolled high blood pressure despite taking antihypertensive medications, consult your doctor. It is important to ensure your blood pressure is under control before starting treatment with Oyavas.

• If you have or have had an aneurysm (a bulge and weakening in the wall of a blood vessel) or a tear in the wall of a blood vessel.

• This medicine increases the risk of protein in the urine, especially if you already have high blood pressure.

• The risk of developing blood clots or thrombi in your arteries (a type of blood vessel) may increase if you are over 65 years old, have diabetes, or have previously had arterial blood clots. Consult your doctor, as blood clots may lead to heart attack or stroke.

• Oyavas may also increase the risk of developing blood clots or thrombi in the veins (a type of blood vessel).

• Oyavas may cause bleeding, particularly tumor-related bleeding. Consult your doctor if you have a personal or family history of bleeding disorders (coagulation disorders) or are taking blood-thinning medications for any reason.

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

• Oyavas may increase the risk of bleeding in your lungs, including coughing up blood or bloody sputum. Consult your doctor if you have previously experienced this.

• Oyavas may increase the risk of heart weakening. It is important to inform your doctor if you have ever been treated with anthracyclines (a specific type of chemotherapy used to treat certain cancers, such as doxorubicin), received chest radiation therapy, or have heart disease.

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

• Oyavas may cause hypersensitivity reactions, including anaphylactic and/or infusion-related reactions (reactions related to the injection of the medicine). Consult your doctor, pharmacist, or nurse if you have previously experienced problems after injections, such as dizziness/fainting, difficulty breathing, swelling, or skin rash.

• A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with treatment with Oyavas. If you experience headache, vision disturbances, confusion, or seizures (convulsions), with or without high blood pressure, consult your doctor.

• Cases of bone tissue death (osteonecrosis) in bones other than the jaw have been reported in patients under 18 years of age treated with Oyavas. Pain in the mouth, teeth, and/or jaw, swelling or sores in the mouth, numbness or heaviness in the jaw, or tooth loss may be signs and symptoms of jaw bone damage (osteonecrosis). Inform your doctor and dentist immediately if you experience any of these.

Please consult your doctor even if any of the situations listed above apply to you or have occurred in the past.

Before starting treatment with Oyavas or during treatment with Oyavas:

• if you have or have had pain in the mouth, teeth, and/or jaw, swelling or sores in the mouth, numbness or heaviness in the jaw, or tooth loss, inform your doctor and dentist immediately.
• if you need invasive dental treatment or dental surgery, inform your dentist that you are being treated with Oyavas, especially if you are also receiving or have received intravenous bisphosphonate injections.

Before starting treatment with Oyavas, you may be advised to have a dental examination.

Oyavas has been developed and manufactured for the treatment of cancer via intravenous injection. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for use in this way. 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, small particles or spots in vision (floaters), eye pain,
• Seeing flashes of light with floaters, progressing to partial vision loss,
• Increased intraocular pressure,
• Bleeding in the eye.

Children and adolescents

The use of Oyavas is not recommended in children and adolescents under 18 years of age, as safety and benefit have not been established in these patients.

Other medicines and Oyavas

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

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

Consult your doctor if you are receiving platinum-based or taxane-based treatment for metastatic breast or lung cancer. These treatments 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 Oyavas if you are pregnant. Oyavas may harm the unborn baby, as it can inhibit the formation of new blood vessels. Your doctor must advise you to use an effective method of contraception during treatment with Oyavas and for at least 6 months after the last dose of Oyavas.

If you are pregnant, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

You must not breastfeed during treatment with Oyavas and for at least 6 months after the last dose of Oyavas, as this medicine may interfere with your baby's growth and development.

Oyavas may affect female fertility. Consult your doctor for further information.

Premenopausal women (women who have menstrual cycles) may notice that their periods become irregular or stop and may experience fertility problems. If you are considering having children, discuss this with your doctor before starting treatment.

Driving and using machines

Oyavas has not been shown to impair your ability to drive or operate tools or machinery. However, drowsiness and fainting have been reported with the use of Oyavas. If you experience symptoms affecting your vision or concentration, or your reaction ability, do not drive or use machines until symptoms resolve.

Oyavas contains sodium and polysorbate 20

This medicine contains less than 1 mmol of sodium (23 mg) per vial; this is essentially “sodium-free.”

This medicine contains 1.6 mg of polysorbate 20 in each 100 mg/4 ml vial and 6.4 mg in each 400 mg/16 ml vial, equivalent to 0.4 mg/ml. Polysorbates may cause allergic reactions. Consult 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 being treated. The recommended dose is 5 mg, 7.5 mg, 10 mg, or 15 mg per kilogram of body weight. Your doctor will prescribe the most appropriate Oyavas dose for your condition, and you will receive Oyavas once every 2 or 3 weeks. The number of infusions you receive will depend on your response to treatment, and you should continue treatment until Oyavas is no longer able to inhibit tumor growth. Your doctor will discuss these aspects 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, either a portion or the entire content of the Oyavas vial will be diluted with sodium chloride solution prior to administration. A doctor or nurse will administer this diluted Oyavas solution as an intravenous infusion (a drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion may be administered over 60 minutes. Subsequent infusions may be given over 30 minutes.

Administration of Oyavas must be temporarily interrupted if you:

• develop severe hypertension requiring treatment with antihypertensive medications,
• experience impaired wound healing after surgery,
• have recently undergone surgery.

Administration of Oyavas must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with antihypertensive medications, or if there is a sudden and severe increase in blood pressure;
• protein in the urine accompanied by body swelling;
• a perforation in the intestinal wall;
• a severe abnormal tubular connection or fistula between the trachea and esophagus (the tube leading to the stomach), between internal organs and the skin, between the vagina and any part of the intestine, or between other tissues that are normally not connected, as determined by your doctor;
• severe skin infections or deep skin layer infections;
• arterial embolism (blood clot in the arteries);
• embolism in the pulmonary blood vessels;
• any severe bleeding.

If you use more Oyavas than you should

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

If you forget to use Oyavas

• your doctor will decide when your next Oyavas dose should be administered. You must inform your doctor about the missed dose.

If you interrupt treatment with Oyavas

Interrupting treatment with Oyavas may reduce its effect on tumor growth. Do not interrupt treatment with Oyavas unless you have discussed it with your doctor.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The adverse effects listed below have been observed when Oyavas is administered with chemotherapy. This does not necessarily mean that these adverse effects were strictly caused by Oyavas.

Allergic reactions

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

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

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

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

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

• • intestinal perforation,
  • bleeding, including pulmonary hemorrhage in patients with non-small cell lung cancer,
  • arterial blockage due to embolism,
  • venous blockage due to embolism,
  • blockage of blood vessels in the lungs due to embolism,
  • venous blockage in the legs due to embolism,
  • heart failure,
  • problems with wound healing after surgery,
  • redness, peeling, sensitivity, pain, or blisters on fingers or feet,
  • decrease in red blood cell count,
  • lack of energy,
  • gastrointestinal disturbances,
  • muscle and joint pain, muscle weakness,
  • dry mouth combined with thirst and/or reduced or dark-colored urine,
  • inflammation of the mucosal lining of the mouth and intestine, lungs and airways, reproductive organs, and urinary tract,
  • sores in the mouth and in the tube connecting the mouth to the stomach, which may be painful and cause difficulty swallowing,
  • pain, including headache, back pain, pelvic pain, and anal region pain,
  • localized pus formation,
  • infection, particularly blood or bladder infection,
  • reduced blood flow to the brain or stroke,
  • drowsiness,
  • nosebleeds,
  • increased heart rate (pulse),
  • intestinal obstruction,
  • abnormal urine test (proteins in urine),
  • difficulty breathing or reduced oxygen levels in the blood,
  • skin infections or infections in deeper skin layers,
  • fistula: an abnormal tubular connection between internal organs and the skin or other tissues that are not normally connected, including connections between the vagina and intestine in patients with cervical cancer,
• allergic reactions (signs may include difficulty breathing, facial redness, skin rash, low or high blood pressure, low oxygen levels in blood, chest pain, or nausea/vomiting).

Serious adverse effects that may be rare (may affect up to 1 in 1000 patients) include:

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

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

• severe skin infections or infections in deeper layers beneath the skin, especially if you had intestinal wall perforations or problems with wound healing,
• negative effect on a woman's ability to have children (see below for further recommendations),
• brain disease with symptoms such as seizures (fits), headache, confusion, and vision disturbances (posterior reversible encephalopathy syndrome or PRES),
• symptoms suggesting changes in normal brain function (headaches, vision disturbances, confusion, or seizures), and high blood pressure,
• enlargement and weakening of the wall of a blood vessel or tear in the wall of a blood vessel (arterial aneurysms and dissections),
• blockage of small blood vessels in the kidney,
• abnormally high pressure in the blood vessels of the lungs causing the right side of the heart to work harder than normal,
• perforation in the cartilage wall separating the nasal openings,
• perforation of the stomach or intestine,
• ulceration or perforation in the lining of the stomach or small intestine (these signs may include abdominal pain, bloating sensation, black stools, bloody stools, or blood in vomit),
• bleeding from the lower part of the large intestine,
• gum lesions with exposed jawbone that do not heal and may be associated with pain and inflammation of surrounding tissues (for further recommendations, see the list of adverse effects in the paragraph below),
• perforation of the gallbladder (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you notice any of these adverse effects listed, seek medical attention as soon as possible.

Adverse effects that are very common (may affect more than 1 in 10 patients) but not serious include:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech disturbances,
• taste disturbances,
• nasal discharge,
• dry, peeling, and inflamed skin, changes in skin color,
• weight loss,
• nosebleeds.

Adverse effects that are common (may affect up to 1 in 10 patients) but not serious include:

• changes in voice and hoarseness.

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

• arterial embolism, which may lead to stroke or heart attack,
• reduction in white blood cell and platelet counts (which aid in clotting) in blood,
• diarrhea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

Oyavas may also cause changes in laboratory tests performed by your doctor. These changes may include a reduction in white blood cell counts, particularly neutrophils (a type of white cell that helps protect against infections), presence of proteins in urine, decreased potassium, sodium, or phosphorus in blood, increased blood sugar, increased alkaline phosphatase (an enzyme) in blood, decreased hemoglobin (found in red blood cells and responsible for oxygen transport), which may be severe.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is an effect not listed in this leaflet. You may also report them directly through the national reporting system detailed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Oyavas

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

Do not use this medicine after the expiry date stated on the carton and on the label of the vial after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (between 2 °C and 8 °C). Do not freeze.

Keep the vial in the outer packaging to protect it from light.

The infusion solution should be administered immediately after dilution. If not administered immediately, the storage times and conditions during use are the responsibility of the user and normally would not exceed 24 hours between 2 °C and 8 °C, unless the infusion solutions have been prepared under sterile conditions. When dilution takes place under sterile conditions, Oyavas will be stable after dilution for up to 30 days when stored between 2 °C and 8 °C, and for up to 48 hours at temperatures not exceeding 30 °C.

Do not use Oyavas if you notice any foreign particles or discoloration before administration.

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

6. Contents of the pack and other information

Composition of Oyavas

• The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 or 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, disodium phosphate, polysorbate 20 (E 432), and water for injections (see section 2 “Oyavas contains sodium and polysorbate 20”).

Appearance of the product and contents of the container

Oyavas is a concentrate for solution for infusion (sterile concentrate). The concentrate is a colourless to brown or pale yellow liquid with opalescence contained in a glass vial with a rubber stopper. Each vial contains 100 mg of bevacizumab in 4 ml of solution or 400 mg of bevacizumab in 16 ml of solution. Each Oyavas pack contains one vial.

Marketing Authorisation Holder

STADA Arzneimittel AG

Stadastrasse 2‑18

61118 Bad Vilbel

Germany

Manufacturer responsible for manufacturing

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:

Date of the most recent review of this leaflet: <{MM/YYYY}><{month YYYY}>.

Other sources of information

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