Avastin 25 mg/ml concentrate for infusion solution

Patient Information Leaflet

Introduction

Package Leaflet: Information for the Patient

Avastin 25mg/ml concentrate for solution for infusion

bevacizumab

Read all of this leaflet carefully before you start using this medicine, as 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, consult your doctor, pharmacist, or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet Contents:

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

1. What Avastin is and what it is used for

The active substance in Avastin 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 in the walls of blood and lymphatic vessels in the body. The VEGF protein causes blood vessels to grow 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.

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

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

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

Avastin 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). In this case, Avastin will be given in combination with erlotinib.

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

Avastin 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, Avastin will be administered 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, Avastin will be administered 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, Avastin will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

Avastin is also used to treat adult patients with persistent, recurrent, or metastatic cervical cancer. Avastin 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 need to know before using Avastin

Do not use Avastin

• if you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic (hypersensitive) to products derived from Chinese Hamster Ovary (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 Avastin

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

• Avastin may increase the risk of developing abnormal connections between two organs or vessels. 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.

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

• Avastin may increase the risk of developing severe skin infections or deep skin layer infections, especially if you have experienced intestinal wall perforation or wound healing problems.

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

• 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 clots or thrombi. Consult your doctor, as clots or thrombi can lead to heart attack and stroke.

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

• This medicine 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.

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

• Avastin 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.

• Avastin 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), have received chest radiation therapy, or have a heart condition.

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

• Avastin 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 Avastin treatment. If you experience headache, vision changes, confusion, or seizures (convulsions), with or without high blood pressure, consult your doctor.

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

Before starting Avastin treatment or during Avastin treatment:

• if you have or have had mouth pain, tooth or jaw pain, 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 Avastin, especially if you are also receiving or have received intravenous bisphosphonate injections.

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

Children and adolescents

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

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

Other medicines and Avastin

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

Combining Avastin with another medicine called sunitinib malate (used for kidney 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 therapy for metastatic breast or lung cancer. These therapies in combination with Avastin may increase the risk of serious adverse effects.

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

Pregnancy, breastfeeding, and fertility

Do not use Avastin if you are pregnant. Avastin can harm the fetus, as it may inhibit the formation of new blood vessels. Your doctor must advise you to use an effective method of contraception during Avastin treatment and for at least 6 months after the last dose of Avastin.

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

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

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

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

Driving and using machines

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

Avastin contains sodium and polysorbate 20

This medicine contains less than 1 mmol of sodium (23 mg) per vial, which 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 Avastin

Dosage and frequency of administration

The required dose of Avastin 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 dose of Avastin most suitable for your condition, and you will receive Avastin once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to treatment, and you should continue treatment until Avastin 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.

Avastin is a concentrate for solution for infusion. Depending on the prescribed dose, either a portion or the entire contents of the Avastin vial will be diluted with sodium chloride solution prior to administration. A doctor or nurse will administer this diluted Avastin 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 Avastin must be temporarily interrupted:

• if you develop severe hypertension requiring treatment with blood pressure medications,
• if you experience wound healing problems after surgery,
• if you have recently undergone surgery.

Administration of Avastin must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with blood pressure 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 wall of the intestine,
• an abnormal tubular or fistulous connection 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 not normally connected (fistula), which your doctor considers serious,
• severe skin infections or deep layers of the skin,
• arterial embolism (blood clot) in the arteries,
• embolism in the pulmonary blood vessels,
• any severe bleeding.

If you use more Avastin 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 Avastin

• your doctor will decide when your next dose of Avastin should be administered. You must inform your doctor about this missed dose.

If you interrupt treatment with Avastin

Interrupting treatment with Avastin may reduce its effect on tumor growth. Do not interrupt treatment with Avastin unless discussed 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.

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects not listed in this leaflet.

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

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, rash, chills and shivering, dizziness (nausea), or feeling unwell (vomiting), swelling, dizziness, rapid heartbeat, or loss of consciousness.

You must seek immediate medical 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,
• numbness or tingling sensation 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 between 1 and 10 in 100 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,
• blockage of leg veins due to embolism,
• heart failure,
• wound healing problems after surgery,
• redness, peeling, sensitivity, pain, or blistering 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 urine output 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 (esophagus), which may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal region pain,
• localized areas of pus,
• infection, particularly blood infection or bladder infection,
• reduced blood supply to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (protein in urine),
• difficulty breathing or reduced oxygen levels in blood,
• skin infections or infections of deeper layers beneath the skin,
• 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 1,000 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 skin layers, especially if you had intestinal wall perforation or wound healing problems,
• negative effect on a woman’s ability to have children (see further recommendations below),
• 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,
• weakening and bulging of a blood vessel wall or blood vessel wall tear (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,
• ulcer 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 below),
• gallbladder perforation (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

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

Non-serious adverse effects that are very common (may affect more than 1 in 10 patients) include:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech disturbances,
• taste disturbances,
• runny nose,
• dry skin, skin peeling, skin inflammation, changes in skin color,
• weight loss,
• nosebleeds.

Non-serious adverse effects that are common (may affect up to 1 in 10 patients) include:

• changes in voice and hoarseness.

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

• arterial embolism that may lead to stroke or heart attack,
• reduction in white blood cells and platelets (which help with blood clotting),
• diarrhea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

Avastin may also cause changes in laboratory tests performed by your doctor. These changes may include reduced white blood cell counts, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in urine, decreased potassium, sodium, or phosphorus levels 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.

Pain in the mouth, teeth, and/or jaw, swelling or sores in the mouth, numbness or heaviness in the jaw, or tooth loss. These may be signs and symptoms of jaw bone damage (osteonecrosis). Inform your doctor and dentist immediately if you experience any of these.

Premenopausal women (women who have menstrual periods) 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.

Avastin 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 this use. When Avastin is injected directly into the eye (off-label use), the following side effects may occur:

• Eye 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.

Reporting of adverse effects

If you experience any adverse effect, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects not listed in this leaflet. You may also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you help provide more information on the safety of this medicine.

5. Storage of Avastin

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 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 solution for infusion 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 at between 2°C and 8°C, unless the infusion solutions have been prepared under sterile conditions. When dilution has been prepared under sterile conditions, Avastin remains stable for 30 days at between 2°C and 8°C plus an additional 48 hours at between 2°C and 30°C.

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

Medicines should 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 Avastin

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, sodium phosphate, polysorbate 20 (E432) (see section 2 “Avastin contains sodium and polysorbate 20”), and water for injections.

Appearance of the medicinal product and contents of the pack

Avastin is a concentrate for solution for infusion. The concentrate is a colourless to pale brown, clear 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 Avastin pack contains one vial.

Marketing Authorization Holder

Roche Registration GmbH
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer

Roche Pharma AG
Emil-Barell-Str. 1
79639 Grenzach-Wyhlen
Germany

Further information on this medicinal product is available upon request by contacting the local representative of the Marketing Authorization Holder:

Date of the most recent review of this leaflet

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.