Patient Information Leaflet

Avastin 25 mg/ml concentrate for solution for infusion

bevacizumab

Read 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, consult your doctor, pharmacist or nurse.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

1.What Avastin is and what it is used for

2.What you need to know before you start using Avastin

3.How to use Avastin

4.Possible side effects

5.Storage of Avastin

6.Contents of the pack and additional information

The active ingredient of Avastin is bevacizumab, a humanized monoclonal antibody (a type of protein that is normally produced by the immune system to help the body defend itself against infections and cancer). Bevacizumab selectively binds to a protein called vascular endothelial growth factor (VEGF, English acronym), which is located in the walls of blood and lymphatic vessels of the body. The VEGF protein causes blood vessels to grow within the tumor, which supplies it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels, which provide the necessary nutrients and oxygen for the tumor.

Avastin is a medication used for the treatment of adult patients with advanced colorectal or rectal cancer. Avastin will be administered in combination with a chemotherapy regimen containing a fluoropyrimidine medication.

Avastin is also used for the treatment of adult patients with metastatic breast cancer. When used in patients with breast cancer, it will be administered with a chemotherapy medication called paclitaxel or capecitabine.

Avastin is also used for the treatment of adult patients with advanced non-small cell lung cancer. Avastin will be administered along with a platinum-based chemotherapy regimen.

Avastin is also used for the treatment of adult patients with advanced non-small cell lung cancer when cancer cells have specific mutations in a protein called the epidermal growth factor receptor (EGFR). Avastin will be administered in combination with erlotinib.

Avastin is also used for the treatment of adult patients with advanced renal cancer. When used in patients with renal cancer, it will be administered with another type of medication called interferon.

Avastin is also used for the treatment of 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, it will be administered in combination with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease for at least 6 months since their last treatment with a platinum-based chemotherapy regimen, Avastin will be administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease for at least 6 months since their last treatment with a platinum-based chemotherapy regimen, Avastin will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

Avastin is also used for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer. Avastin will be administered in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum-based therapy.

No use Avastin

• If you are allergic (hypersensitive) to bevacizumab or any of the other components of this medication (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

Consult your doctor, pharmacist, or nurse before starting to use Avastin.

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

• Avastin may increase the risk of developing an abnormal communication between two organs or vesicles. The risk of developing communications between the vagina and any part of the intestine may increase if you have persistent, recurrent, or metastatic cervical cancer.

• This medication may increase the risk of bleeding or problems with wound healing. If you are to be operated on, have had major surgery in the last 28 days, or have an unhealed surgical wound, do not use this medication.

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

• Avastin may increase the risk of hypertension. If you have uncontrolled high blood pressure, consult your doctor, it is essential to ensure that your blood pressure is controlled before starting treatment with Avastin.

• If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.
• This medication increases the risk of having protein in the urine, especially if you already have high blood pressure.

• The risk of developing thrombi or clots 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 thrombi or clots in your arteries in the past. Consult your doctor, as thrombi or clots can cause heart attack and stroke.

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

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

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

• Avastin may increase the risk of bleeding in your lungs, including coughing or expectoration of blood. Consult your doctor if you have noticed this previously.

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

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

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

• A rare neurological side effect called reversible posterior leukoencephalopathy syndrome (RPLS) has been associated with Avastin treatment. If you have headaches, vision changes, confusion, or seizures (convulsions) with or without high blood pressure, consult your doctor.

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

Before starting treatment with Avastin or during treatment with Avastin:

• If you have or have had mouth pain, tooth pain, or gum pain, swelling, or sores in the mouth, numbness, or a feeling of heaviness in the jaw, or tooth loss, inform your doctor and dentist immediately.
• If you need to undergo invasive dental treatment or surgery, inform your dentist that you are being treated with Avastin, especially when you are also receiving or have received an injection of bisphosphonates in your blood.

You may be advised to have a dental check-up before starting treatment with Avastin.

Children and adolescents

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

Cases of osteonecrosis (death of bone tissue) in bones other than the jaw have been reported in patients under 18 years old treated with Avastin.

Other medications and Avastin

Inform your doctor, pharmacist, or nurse if you are using, have used recently, or may need to use any other medication.

The combination of Avastin with another medication called sunitinib malate (prescribed for renal and gastrointestinal cancer) may cause severe side effects. Consult your doctor to ensure that you do not combine these medications.

Consult your doctor if you are receiving treatment based on platinum or taxanes for metastatic breast or lung cancer. These therapies combined with Avastin may increase the risk of severe side effects.

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

Pregnancy, breastfeeding, and fertility

You should not use Avastin if you are pregnant. Avastin may harm the fetus, as it may slow down the formation of new blood vessels. Your doctor should advise you to use a contraceptive method during treatment with Avastin and at least 6 months after the last dose of Avastin.

Inform your doctor immediately if you are already pregnant, become pregnant during treatment with Avastin, or plan to become pregnant in the future.

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

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

Consult your doctor, pharmacist, or nurse before using any medication.

Driving and operating machinery

Avastin has not been observed to decrease your ability to drive or operate tools or machines. However, drowsiness and fainting have been reported with the use of Avastin. If you experience symptoms that affect your vision or concentration, or your reaction time, do not drive or operate machines until the symptoms disappear.

Important information about some ingredients in Avastin

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

Dosage and Administration Frequency

The dosage of Avastin required depends on your weight and the type of cancer being treated. The recommended dosage is 5mg, 7.5mg, 10mg or 15mg per kilogram of body weight. Your doctor will prescribe the most suitable dosage of Avastin for your case, and you will be treated with Avastin once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to the treatment and you should continue it until Avastin can no longer slow down tumor growth. Your doctor will discuss these aspects with you.

Form and Route of Administration

Do not shake the vial.

Avastin is a concentrated solution for infusion. Depending on the dosage prescribed, a fraction or the entire contents of the Avastin vial will be diluted with sodium chloride solution before administration. A doctor or nurse will administer this diluted Avastin solution as an intravenous infusion (through a drip in your veins). The first infusion will be administered over 90 minutes. If you tolerate this infusion well, the second can be administered over 60 minutes. Subsequent infusions can be administered over 30 minutes.

Avastin Administration Must Be Temporarily Interrupted:

• if you develop severe hypertension that requires treatment with antihypertensive medications,
• if you have wound healing problems after surgery,
• if you have undergone surgery.

Avastin Administration Must Be Permanently Suspended If You Have:

• severe hypertension that cannot be controlled with antihypertensive medications; or in the event of a sudden and severe increase in blood pressure,
• protein in the urine accompanied by body swelling,
• a perforation in the intestinal wall,
• an abnormal communication of a tubular or fistulous type between the trachea and esophagus (the tube that leads 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 (fistula), and which your doctor considers severe,
• severe skin or deep skin layer infections,
• arterial embolism (blood clot),
• pulmonary vein embolism,
• any severe hemorrhage.

If You Use More Avastin Than You Should

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

If You Forget to Use Avastin

• Your doctor will decide when the next dose of Avastin should be administered. You must inform your doctor of this oversight.

If You Interrupt Avastin Treatment

Interrupting Avastin treatment may suppress its effect on tumor growth. Do not interrupt Avastin treatment unless you have consulted with your doctor.

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

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

If you experience side effects, consult your doctor, pharmacist, or nurse, even if they are side effects that do not appear in this leaflet.

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

Allergic reactions

If you have an allergic reaction, consult your doctor or healthcare professional immediately. Symptoms may include: difficulty breathing or chest pain. You may also experience skin redness or flushing, hives, chills, and tremors, dizziness or nausea, swelling, dizziness, tachycardia, loss of consciousness.

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

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

• high blood pressure,
• sensation 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 to clot,
• sensation of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Severe side effects that may be frequent (may affect up to 1 in 100 patients) include:

• intestinal perforation,
• bleeding, including pulmonary hemorrhage in patients with non-small cell lung cancer,
• arterial embolism,
• venous embolism,
• embolism of pulmonary vessels,
• embolism of leg veins,
• heart failure,
• problems with wound healing after surgery,
• skin redness, peeling, sensitivity, pain, or blisters on fingers or feet,
• decrease in red blood cell count,
• lack of energy,
• gastrointestinal and intestinal alterations,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced urine output or dark-colored urine,
• inflammation of the mucous membrane of the mouth, intestines, lungs, and airways, reproductive system, and urinary tract,
• mouth sores and esophageal tube that may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal pain,
• localized pus foci,
• infection, and particularly blood or urinary tract infection,
• decrease in cerebral blood flow or apoplexy,
• drowsiness,
• nasal bleeding,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (proteins in urine),
• difficulty breathing or decreased oxygen levels in blood,
• skin or deep tissue infections,
• fistula: abnormal communication of a tubular type between internal organs and the skin or other tissues that are normally not connected, including communication between the vagina and intestines in patients with cervical cancer.
• allergic reactions (symptoms may include difficulty breathing, facial redness, skin rash, low or high blood pressure, low oxygen levels in blood, chest pain, or nausea/vomiting),

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

• severe skin or deep tissue infections, especially if you had intestinal perforations or wound healing problems,
• negative effect on a woman's ability to have children (see below for more recommendations),
• brain disease with symptoms such as seizures (convulsions), headache, confusion, and vision changes (Reversible Posterior Leukoencephalopathy Syndrome or RPLS),
• symptoms suggesting changes in normal brain function (headache, vision changes, confusion, or convulsions), and high blood pressure,
• increase and weakening of the wall of a blood vessel or rupture 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 pulmonary vessels that makes the right side of the heart work harder than normal,
• perforation in the cartilage wall that separates the nasal openings,
• perforation in the stomach or intestine,
• ulcer or perforation in the stomach or small intestine lining (these symptoms may include abdominal pain, sensation of swelling, black stools, stools with blood, 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 (see below for more recommendations),
• perforation of the gallbladder (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you experience any of these side effects mentioned, seek medical attention as soon as possible.

Side effects that are very frequent (may affect more than 1 in 10 patients) that are not severe are:

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

Side effects that are frequent (may affect up to 1 in 10 patients) that are not severe are:

• voice changes and hoarseness.

Patients over 65 years old have a higher risk of experiencing the following:

• embolism in the arteries that may cause apoplexy or heart attack,
• decrease in white blood cell and platelet count (which helps blood to clot) in blood,
• diarrhea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

Avastin may also cause changes in laboratory tests that your doctor will perform. These changes may include a decrease in white blood cell count, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of proteins in urine, decrease in potassium, sodium, or phosphorus in blood, increase in blood sugar, increase in alkaline phosphatase (an enzyme) in blood, decrease in hemoglobin (which is found in red blood cells and transports oxygen), which may be severe.

Mouth pain, teeth, and/or jaw pain, swelling, or sores in the mouth, numbness or heaviness of the jaw, or tooth loss. These may be signs and symptoms of jawbone damage (osteonecrosis). Immediately report to your doctor and dentist if you experience any of them.

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

Avastin has been developed and manufactured to treat cancer through 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 Avastin is injected directly into the eye (unapproved use), the following side effects may occur:

• infection or inflammation of the eyeball,
• eye redness, small particles or spots in vision (floaters), eye pain,
• vision of flashes of light with floaters, progressing to partial vision loss,
• increased intraocular pressure,
• bleeding in the eye.

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the national notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the packaging and on the vial label after CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C).

Do not freeze.

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

The infusion solution must be administered immediately after dilution. If it is not administered immediately, the storage times and conditions in use are the responsibility of the user and are normally not more than 24 hours between 2°C and 8°C, unless the infusion solutions have been prepared in a sterile environment. When the dilution has been prepared in a sterile environment, Avastin remains stable for 30 days between 2°C and 8°C plus an additional 48 hours between 2°C and 30°C.

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

Medications should not be disposed of through drains or trash. Ask your pharmacist how to dispose of the packaging and medications that you do not need. This will help protect the environment..

Composition of Avastin

The active ingredient is bevacizumab.

• Each milliliter of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 or 16.5 mg/ml when diluted as recommended.

Each vial of 4 ml contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.

Each vial of 16 ml contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.

• The other components are trehalose dihydrate, sodium phosphate (see section 2 Important information about some ingredients of Avastin), polisorbate 20, and water for injection.

Appearance of the product and contents of the package

Avastin is a concentrate for solution for infusion. The concentrate is a transparent, colorless to pale brown liquid contained in a glass vial 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 package of Avastin contains one vial.

Marketing authorization holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Responsible for manufacturing

Roche Pharma AG

Emil-Barell-Str. 1

79639 Grenzach-Wyhlen

Germany

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

Last update of this leaflet

Other sources of information

The detailed information about this medicine is available on the website of the European Medicines Agency http://www.ema.europa.eu .