Avastin

Package Leaflet: Information for the User

Avastin 25 mg/mL concentrate for solution for infusion

bevacizumab
Please read this leaflet carefully before 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 side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Avastin is and what it is used for
2. What you need to know before using 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

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

Avastin is a medicine used to treat adult patients with advanced carcinoma of the large intestine, i.e. colon or rectal cancer. Avastin will be administered in combination with a fluoropyrimidine-based chemotherapy regimen.

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

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

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

Avastin is also used to treat adult patients with advanced renal cell carcinoma. In patients with this type of tumour, Avastin will be administered together with another type of medicine called interferon.

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

Avastin will be administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel when used in adult women with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer whose disease has recurred at least 6 months after the last time they were treated with a platinum-containing chemotherapy regimen.

Avastin will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin when used in adult women with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer whose disease has recurred within 6 months of the last time they were treated with a platinum-containing chemotherapy regimen.

Avastin is also used to treat adult women with persistent, recurrent, or metastatic cervical cancer. Avastin will be administered in combination with paclitaxel and cisplatin or, alternatively, with paclitaxel and topotecan in women 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 developing intestinal wall perforations. If you have conditions causing abdominal inflammation (e.g. diverticulitis, gastric ulcers, chemotherapy-associated colitis), discuss this with your doctor.
∙ Avastin may increase the risk of developing abnormal connections or passages between two organs or blood vessels. Persistent, recurrent, or metastatic cervical carcinoma may increase the risk of developing connections between the vagina and any part of the gastrointestinal tract.
∙ This medicine may increase the risk of bleeding or impair wound healing after surgery. Do not take this medicine if you are scheduled for surgery, if you have undergone major surgery within the past 28 days, or if you have a surgical wound that has not yet healed.
∙ Avastin 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.
∙ Avastin 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 Avastin.
∙ 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 having 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 a history of previous arterial blood clots. Discuss this with your doctor, as blood clots can lead to heart attacks and strokes.
∙ Avastin may also increase the risk of developing blood clots in veins (a type of blood vessel).
∙ This medicine may cause bleeding, particularly tumor-related bleeding. Consult your doctor if you or members of your family have a history of bleeding disorders or if you are taking blood-thinning medications for any reason.
∙ Avastin may cause bleeding within or around the brain. Consult your doctor if you have brain metastases.
∙ Avastin 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.
∙ Avastin may increase the risk of developing heart failure. It is important that your doctor knows if you have previously received anthracycline therapy (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).
∙ Avastin may cause hypersensitivity reactions (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 reversible posterior encephalopathy syndrome (PRES) has been associated with Avastin treatment. If you experience headache, vision disturbances, confusion, or seizures with or without elevated blood pressure, contact your doctor immediately. Also seek medical advice if any of these symptoms occurred in the past.

Before starting or during treatment with Avastin:
∙ if you have had or currently have mouth, tooth, and/or jaw pain, swelling or inflammation in the mouth, numbness or a feeling of heaviness in the jaw, or lose a tooth, inform your doctor and dentist immediately;
∙ if you need to undergo invasive dental procedures or dental surgery, inform your dentist that you are being treated with Avastin, especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting Avastin treatment.

Children and adolescents
Avastin therapy is not recommended in children and adolescents under 18 years of age, as neither safety nor efficacy has been established in this patient population.
Bone tissue death (osteonecrosis) in bones other than the jaw has been observed 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 take any other medicines.
Combining Avastin with another medicine called sunitinib malate (used for kidney and gastrointestinal cancers) may cause severe adverse effects. Discuss with your doctor to ensure these medicines are not used together.
Inform your doctor if you are receiving platinum-based or taxane therapies for metastatic lung or breast cancer. These therapies in combination with Avastin may increase the risk of severe side effects.
Inform your doctor if you have recently received or are currently receiving radiotherapy.

Pregnancy, breastfeeding, and fertility
Do not use Avastin if you are pregnant. Avastin may harm the unborn child, as it can interfere with the formation of new blood vessels. Your doctor will advise you to use effective contraception during treatment with Avastin and for at least 6 months after the last dose.
If you are pregnant, suspect you are pregnant during treatment with this medicine, or are planning a pregnancy in the near future, speak to your doctor immediately.
You must not breastfeed during treatment with Avastin and for at least 6 months after the last dose, as Avastin may interfere with the baby’s growth and development.
Avastin may reduce female fertility. Consult your doctor for further information.
Ask your doctor, pharmacist, or nurse for advice before taking any medicine.

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

Avastin contains sodium and polysorbate 20
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e., 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.
Inform 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 tumour 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 Avastin at the dose appropriate for you. Treatment with Avastin will be administered once every 2 or 3 weeks. The number of infusions you receive will depend on your response to treatment; however, you should continue receiving this treatment until Avastin is no longer able to block the growth of your tumour. Your doctor will discuss this with you.

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

Temporary interruption of Avastin administration is required if
∙ severe high blood pressure develops, requiring treatment with medicines to control blood pressure,
∙ you experience problems with wound healing after surgery,
∙ you need to undergo a surgical procedure.

Avastin administration must be permanently discontinued if any of the following problems 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 oedema (swelling of the body),
∙ perforation of the intestinal wall,
∙ an abnormal connection or passage between the trachea and oesophagus, internal organs and skin, vagina and any part of the gastrointestinal tract, or between other tissues not normally connected (fistula), as judged by the doctor to be severe,
∙ severe infections of the skin or deeper layers beneath the skin,
∙ blood clots in the arteries,
∙ blood clots in the blood vessels of the lungs,
∙ severe bleeding of any kind.

If too much Avastin is administered
∙ you may experience a severe headache. In this case, contact your doctor, pharmacist or nurse immediately.

If you forget to receive a dose of Avastin
∙ your doctor will decide the most appropriate time for you to receive the next dose of Avastin. Discuss this with your doctor.

If you stop treatment with Avastin
Stopping treatment with Avastin may cause the inhibition of tumour growth to cease. Do not stop treatment with Avastin without first discussing it with your doctor.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse.
The side effects listed below have been observed in patients treated with Avastin in combination with chemotherapy. This does not mean that these side effects were necessarily caused by Avastin.

Allergic reactions
If you experience an allergic reaction, tell your doctor or a healthcare professional immediately. Signs may include: difficulty breathing or chest pain. Other possible symptoms include skin redness or flushing, rash, chills and tremors, feeling unwell (nausea) or vomiting, swelling, dizziness, 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,
• numbness or tingling sensation in the hands or feet,
• reduction in blood cells, including white blood cells (which 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 bleeding in patients with non-small cell lung cancer,
• blocked arteries due to blood clots,
• blocked veins due to blood clots,
• blocked pulmonary blood vessels due to blood clots,
• blocked leg veins due to blood clots,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, soreness, pain or blistering on the palms of the hands or soles of the feet,
• reduction in the number of red blood cells,
• lack of energy,
• stomach and intestinal disturbances,
• 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 and airways, reproductive and urinary tract,
• mouth and oesophageal ulcers that may cause pain and difficulty swallowing,
• pain, including headache, back pain, and pain in the pelvic area and around the anus,
• localized abscesses,
• infections, particularly blood or bladder infections,
• reduced blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (palpitations),
• intestinal obstruction,
• abnormal urine test results (presence of protein in the urine),
• shortness of breath or reduced 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 that are 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:

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

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

• severe skin infections or infections in deeper skin layers, particularly if you have had intestinal wall perforation or problems with wound healing,
• 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 (PRES)),
• symptoms suggesting changes in normal brain function (headache, visual disturbances, confusion or seizures) and high blood pressure,
• dilation and weakening of a blood vessel wall or a tear in a 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 intestine,
• an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, bloating sensation, 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 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.

Side effects that are very common (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, or inflamed skin, skin colour changes,
• weight loss,
• nosebleeds.

Side effects that are common (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.

Avastin may also cause changes in laboratory test results prescribed by your doctor. These include: reduced number of white blood cells, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in the urine, reduced levels of potassium, sodium or phosphorus (a mineral) in the blood, increased blood glucose levels, 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.

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

Premenopausal women (women who have menstrual periods) may experience menstrual irregularities, absence of menstruation, and may experience negative effects on fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.

Avastin has been developed and manufactured for cancer treatment via intravenous injection. It has not been developed or manufactured for administration by injection into the eye. Therefore, this route of administration is not authorised. When Avastin is injected directly into the eye (unapproved use), the following side effects may occur:

• eye infection or inflammation of the eyeball,
• eye redness, appearance of floating particles or spots in the visual field ("floaters"), eye pain,
• flashes of light and "floaters" progressing to partial loss of visual field,
• increased eye pressure,
• eye haemorrhage.

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

5. How to store Avastin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and on the vial label after the abbreviation “Exp./EXP”. The expiry date refers to the last day of the 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 immediate use is not possible, the user is responsible for the storage duration and conditions, which normally should not exceed 24 hours at a temperature of 2 °C to 8 °C, unless the infusion solutions have been prepared under sterile conditions. If dilution has been carried out under sterile conditions, Avastin is stable for 30 days at 2 °C to 8 °C and an additional 48 hours at 2 °C to 30 °C.
Do not use Avastin if particulate matter or colour changes are observed 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. Package contents and other information

What Avastin 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, sodium phosphate, polysorbate 20 (E 432) (see section 2 “Avastin contains sodium and polysorbate 20”), and water for injections.

Description of the appearance of Avastin and contents of the pack
Avastin is a concentrate for solution for infusion. The concentrate is a clear, colourless to light brown liquid in a glass vial closed 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 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

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

België/Belgique/Belgien, Latvija, Luxembourg/Luxemburg
Roche Latvija SIA
N.V. Roche S.A.
Tel: +32 (0) 2 525 82 11
Tel: +371 - 6 7039831

България, Lietuva
Roche Bulgaria EOOD
Tel: +359 2 474 5444
UAB “Roche Lietuva”
Tel: +370 5 2546799

Česká republika, Magyarország
Roche s.r.o.
Tel: +420 - 2 20382111
Roche (Magyarország) Kft.
Tel: +36 1 279 4500

Danmark, Nederland
Roche Pharmaceuticals A/S
Tlf: +45 - 36 39 99 99
Roche Nederland B.V.
Tel: +31 (0) 348 438050

Deutschland, Norge
Roche Pharma AG
Tel: +49 (0) 7624 140
Roche Norge AS
Tlf: +47 - 22 78 90 00

Eesti, Österreich
Roche Eesti OÜ
Tel: +372 - 6 177 380
Roche Austria GmbH
Tel: +43 (0) 1 27739

Ελλάδα, Kύπρος
Roche (Hellas) A.E.
Tel: +30 210 61 66 100

España, Portugal
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00

France, România
Roche
Tél: +33 (0) 1 47 61 40 00
Roche România S.R.L.
Tel: +40 21 206 47 01

Hrvatska, Slovenija
Roche d.o.o.
Tel: +385 1 47 22 333
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00

Ireland, Malta, Slovenská republika
Roche Products (Ireland) Ltd.
Ireland/L-Irlanda
Tel: +353 (0) 1 469 0700
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201

Ísland, Suomi/Finland
Roche Pharmaceuticals A/S
c/o Icepharma hf
Sími: +354 540 8000
Roche Oy
Puh/Tel: +358 (0) 10 554 500

Italia, Sverige
Roche S.p.A.
Tel: +39 - 039 2471
Roche AB
Tel: +46 (0) 8 726 1200

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.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATIONS

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for bevacizumab, the PRAC's scientific conclusions are as follows:
In view of the available data on hyaline glomerular occlusive microangiopathy reported in the literature, including some cases with positive dechallenge, and in view of a plausible mechanism of action, the PRAC considers that a causal relationship between bevacizumab and hyaline glomerular occlusive microangiopathy is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing bevacizumab should therefore be amended accordingly.

Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with its overall conclusions and the rationale for the recommendation.

Grounds for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions on bevacizumab, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing bevacizumab remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).