OYAVAS 25 mg/ml CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you use Oyavas

Do not use Oyavas

• if you are allergic (hypersensitive) to bevacizumab or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic (hypersensitive) to products 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 you start using Oyavas

• Oyavas may increase the risk of perforation in the wall of the intestine. If you have any disease that causes 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 sacs. The risk of developing a connection between the vagina and any part of the intestine may increase if you have persistent, recurrent, or metastatic cervical cancer.

• Oyavas may increase the risk of bleeding or problems with wound healing after surgery. If you are going to have surgery, have had major surgery in the last 28 days, or have an unhealed surgical wound, you should not use this medicine.

• Oyavas may increase the risk of developing serious infections of the skin or deep layers of the skin, especially if you have had perforation in the wall of the intestine or problems with wound healing.

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

• 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 or blockages in your arteries (a type of blood vessel) may increase if you are over 65 years old, if you have diabetes, or if you have had blood clots or blockages in your arteries in the past. Consult your doctor, as blood clots or blockages can cause a heart attack and stroke.

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

• Oyavas may cause bleeding, especially bleeding related to the tumor. Consult your doctor if you have a tendency or family history of bleeding disorders or are taking medicines that thin the blood for any reason.

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

• Oyavas may increase the risk of bleeding in your lungs, including coughing up blood. Consult your doctor if you have noticed this before.

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

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

• Oyavas may cause hypersensitivity, including anaphylactic reactions 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 have a headache, changes in vision, confusion, or seizures with or without high blood pressure, consult your doctor.

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

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

Before starting treatment with Oyavas or during treatment with Oyavas:

Before you start treatment with Oyavas, you may be advised to have a dental check-up.

Oyavas has been developed and manufactured to treat cancer by injection into the bloodstream. 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 (unapproved use), the following side effects may occur:

• Infection or inflammation of the eyeball,
• Redness of the eye, small particles or spots in the vision (floaters), eye pain,
• Flashes of light with floaters, progressing to partial loss of vision,
• Increased eye pressure,
• Bleeding in the eye.

Children and adolescents

Oyavas is not recommended for use in children and adolescents under 18 years old, as the safety and efficacy in these patients have not been established.

Other medicines and Oyavas

Tell your doctor, pharmacist, or nurse if you are using, have recently used, or might use any other medicines.

The combination of Oyavas with another medicine called sunitinib malate (prescribed for kidney or gastrointestinal cancer) may cause serious side effects. Consult your doctor to ensure that 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 side effects.

Tell your doctor if you have recently received or are receiving radiation therapy.

Pregnancy, breastfeeding, and fertility

You must not use Oyavas if you are pregnant. Oyavas may harm the unborn baby, as it may prevent the formation of new blood vessels. Your doctor must advise you to use a contraceptive method 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 your baby during treatment with Oyavas and for at least 6 months after the last dose of Oyavas, as this medicine may interfere with the growth and development of your baby.

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

Pre-menopausal women (women who have a menstrual cycle) may notice that their periods become irregular or stop and may experience fertility problems. If you are thinking of having children, you should consult your doctor before starting treatment.

Driving and using machines

Oyavas has not been shown to reduce your ability to drive or use tools or machines. However, somnolence and fainting have been reported with the use of Oyavas. If you experience symptoms that affect your vision or concentration, or your reaction ability, do not drive or use machines until the symptoms disappear.

Oyavas contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per vial, which is essentially "sodium-free".

3. How to use Oyavas

Dose and frequency of administration

The dose of Oyavas needed depends on your 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 suitable dose of Oyavas for you, and you will be treated with Oyavas once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to treatment and should continue until Oyavas can no longer slow down the growth of the tumor. Your doctor will discuss these aspects with you.

Form and route of administration

Do not shake the vial. Oyavas is a concentrate for solution for infusion. Depending on the dose prescribed for you, a fraction or the entire contents of the Oyavas vial will be diluted with sodium chloride solution before administration. A doctor or nurse will administer this diluted Oyavas solution as an intravenous infusion (by drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion can be given over 60 minutes. Subsequent infusions can be given over 30 minutes.

Administration of Oyavas should be temporarily interrupted:

Administration of Oyavas should be permanently stopped if you have:

• severe high blood pressure that cannot be controlled with blood pressure medicines; or if there is a sudden and severe increase in blood pressure,
• protein in the urine accompanied by swelling of the body,
• a perforation in the wall of the intestine,
• an abnormal connection between the trachea and esophagus (the tube that goes to the stomach), between internal organs and the skin, between the vagina and any part of the intestine, or between other tissues that are not normally connected (fistula), and your doctor considers it serious,
• serious infections of the skin or deep layers of the skin,
• blood clots in the arteries,
• blood clots in the blood vessels of the lungs,
• any severe bleeding.

If you use more Oyavas than you should

• you may have severe migraine. If this happens, you should inform your doctor, pharmacist, or nurse immediately.

If you forget to use Oyavas

• your doctor will decide when you should receive the next dose of Oyavas. You should inform your doctor about the missed dose.

If you stop treatment with Oyavas

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

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The adverse effects mentioned 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 have an allergic reaction, consult your doctor or healthcare professional immediately. The signs may include: difficulty breathing or chest pain. You may also experience redness or flushing of the skin or rash, chills and tremors, feeling of dizziness (nausea) or feeling of discomfort (vomiting), swelling, dizziness, tachycardia, loss of consciousness.

You should seek help immediately if you suffer from any of the adverse effects mentioned below.

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

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

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

• allergic reactions (the signs may include difficulty breathing, redness of the face, skin rash, low or high blood pressure, low oxygen levels in the blood, chest pain or nausea/vomiting),
• • perforation of the intestine,
  • bleeding, including hemorrhage in the lungs in patients with non-small cell lung cancer,
  • blockage of the arteries by embolism,
  • blockage of the veins by embolism,
  • blockage of the blood vessels in the lungs by embolism,
  • blockage of the veins in the legs by embolism,
  • heart failure,
  • problems with wound healing after surgery,
  • redness, peeling, sensitivity, pain, or blisters on the fingers or toes,
  • decrease in the number of red blood cells,
  • lack of energy,
  • stomach and intestinal disorders,
  • muscle and joint pain, muscle weakness,
  • dry mouth combined with thirst and/or reduced or dark urine output,
  • inflammation of the mucous membrane lining of the mouth and intestine, lungs and airways, reproductive system and urinary tract,
  • sores in the mouth and the tube that goes from the mouth to the stomach, which can be painful and cause difficulty swallowing,
  • pain, including headache, back pain, in the pelvis and anal regions,
  • localized abscesses,
  • infection, and in particular infection in the blood or bladder,
  • decrease in blood flow to the brain or stroke,
  • drowsiness,
  • nosebleeds,
  • increased heart rate (pulse),
  • intestinal obstruction,
  • abnormal urine test (protein in the urine),
  • difficulty breathing or decrease in oxygen levels in the blood,
  • skin or subcutaneous tissue infections,
  • fistula: abnormal tubular communication between internal organs and the skin or other tissues that are not normally connected, including communications between the vagina and intestine in patients with cervical cancer.

Severe 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, tachycardia, sweating, and loss of consciousness (anaphylactic shock).

Severe adverse effects of unknown frequency(cannot be estimated from the available data) include:

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

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

Very frequent adverse effects (may affect more than 1 in 10 patients) that were not severe are:

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

Frequent adverse effects (may affect up to 1 in 10 patients) that were not severe are:

• changes in voice and hoarseness.

Patient over 65 years of age have a higher risk of experiencing the following:

• embolism in the arteries that can cause stroke or heart attack,
• reduction in the number of white blood cells and platelets (which help with blood clotting) in the blood,
• diarrhea,
• discomfort,
• headache,
• fatigue,
• high blood pressure.

Oyavas may also cause changes in laboratory tests that your doctor performs. These changes may include a reduction in the number of white blood cells in the blood, in particular neutrophils (a type of white blood cell that helps protect against infections), presence of protein in the urine, decrease in potassium, sodium, or phosphorus in the blood, increase in blood sugar, increase in alkaline phosphatase (an enzyme) in the blood, decrease in hemoglobin (which is found in red blood cells and carries oxygen), which can be severe.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is an adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing 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 expiration date that appears on the packaging and on the label of the vial after EXP. The expiration date is 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 solution for infusion should be administered immediately after dilution. If it is not administered immediately, the storage times and conditions are the responsibility of the user and would normally not be more than 24 hours between 2 °C and 8 °C, unless the infusion solutions have been prepared in a sterile environment. When dilution takes place in a sterile environment, Oyavas will be stable after dilution for a period of up to 30 days stored between 2 °C and 8 °C and for a period of up to 48 hours at temperatures not exceeding 30 °C.

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

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

6. Package Contents and Additional Information

Oyavas Composition

• The active ingredient 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, sodium phosphate monobasic monohydrate, disodium phosphate, polysorbate 20, and water for injectable preparations (see section 2 "Oyavas contains sodium").

Product Appearance and Package Contents

Oyavas is a concentrate for solution for infusion (sterile concentrate). The concentrate is a colorless 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 package of Oyavas contains one vial.

Marketing Authorization 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

or

STADA Arzneimittel AG

Stadastrasse 2‑18

61118 Bad Vilbel

Germany

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of the last revision of this leaflet: <{MM/AAAA}><{month AAAA}>.

Other Sources of Information

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