AVASTIN 400 mg Infusion Solution

Зміст інструкції

1. Avastin 25 mg/mL concentrate for solution for infusion
   1. What is Avastin and what is it 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. Package Contents and Other Information

Avastin 25 mg/mL concentrate for solution for infusion

bevacizumab

Read this leaflet carefully before using this medicine as 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 any side effects occur, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4

Contents of 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 is Avastin and what is it used for

Avastin contains the active substance bevacizumab, a humanized monoclonal antibody (a type of
protein that is normally produced by the immune system to help the body defend itself
against infection and cancer). Bevacizumab selectively binds 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 causes the growth of blood vessels within the
tumor; these blood vessels supply the tumor with nutrients and oxygen. Once
bevacizumab binds to VEGF, tumor growth is prevented by blocking the development of the blood
vessels that supply nutrients and oxygen to the tumor.
Avastin is a medicine used for the treatment of adult patients with advanced
colorectal cancer, i.e. of the colon or rectum. Avastin will be administered in combination with a
chemotherapy regimen based on fluoropyrimidines.
Avastin is also used for the treatment of adult patients with metastatic breast cancer. In patients with this type of cancer Avastin will be administered with a chemotherapy regimen based on paclitaxel or capecitabine.
Avastin is also used for the treatment of adult patients with advanced non-small cell lung cancer. Avastin will be administered together with a chemotherapy regimen based on
platinum.
Avastin is also used for the treatment of adult patients with advanced non-small cell lung cancer when the tumor cells present certain mutations of a protein
called 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 kidney cancer.
In patients with this type of cancer Avastin will be administered with another type of medicine
called interferon.
Avastin is used also for the treatment of adult patients affected by epithelial ovarian cancer,
fallopian tube cancer or primary peritoneal cancer in an advanced stage. In patients
with these types of cancer Avastin will be administered in association with carboplatin and paclitaxel.
Avastin will be administered in association with carboplatin and gemcitabine or carboplatin and paclitaxel
when used in adult patients with epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in an advanced stage whose disease has recurred at least 6
months after the last time they were treated with a chemotherapy regimen containing a platinum-based agent.
Avastin will be administered in association with paclitaxel, topotecan or liposomal pegylated doxorubicin
when used in adult patients affected by epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in an advanced stage whose disease has recurred
within 6 months of the last time they were treated with a chemotherapy regimen containing a
platinum-based agent.
Avastin is also used for the treatment of adult patients affected by persistent, recurrent or metastatic cervical cancer. Avastin will be administered in association with paclitaxel and
cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot undergo
platinum-based therapy.

2. What you need to know before you use 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 humanized or human 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 perforations in the intestinal wall. If you have conditions that cause inflammation in the abdomen (e.g. diverticulitis, gastric ulcers, chemotherapy-associated colitis), discuss this with your doctor.
• Avastin may increase the risk of developing an abnormal connection or passage between two organs or vessels. The presence of persistent, recurrent or metastatic cervical carcinoma may determine an increased risk of developing connections between the vagina and any section of the gastrointestinal tract.
• This medicine may increase the risk of bleeding or increase the risk of problems with wound healing after surgery. If you are to undergo surgery, if you have had major surgery in the last 28 days or if you have a surgical wound that has not yet healed, you should not take this medicine.
• Avastin may increase the risk of developing severe skin infections or infections of deeper layers under the skin, especially if you have perforations in the intestinal wall or have problems with wound healing.
• Avastin may increase the incidence of high blood pressure. If you suffer from high blood pressure that is not well controlled with blood pressure medications, discuss this with your doctor. It is important to ensure that your blood pressure is under control before starting treatment with Avastin.
• If you have or have had an aneurysm (dilation and weakening of the wall of a blood vessel) 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 suffer from high blood pressure.
• The risk of developing blood clots in the arteries (a type of blood vessel) may increase if you are over 65 years of age, if you have diabetes and if you have had previous blood clots in the arteries. Talk to your doctor because blood clots can lead to heart attacks and strokes.
• Avastin may also increase the risk of developing blood clots in the veins (a type of blood vessel).
• This medicine can cause bleeding, in particular bleeding related to the tumor. Consult your doctor if you or other family members tend to suffer from coagulation problems or if you are taking medicines to thin the blood for any reason.
• Avastin may cause bleeding inside the brain and around the brain. Consult your doctor if you have a metastatic tumor that affects the brain.
• Avastin may increase the risk of bleeding in the lungs, including blood in the cough or saliva. Discuss with your doctor if you have noticed these events in the past.
• Avastin may increase the risk of developing heart failure. It is important that your doctor knows if you have previously undergone anthracycline therapy (e.g. doxorubicin, a particular type of chemotherapy used to treat some tumors) or thoracic radiotherapy, or if you have heart disease.
• This medicine can cause infections and a reduction in the number of neutrophils (a type of blood cell important for protection against bacteria).
• Avastin may cause hypersensitivity (including anaphylactic shock) and/or infusion reactions (reactions related to the injection of the medicine). Inform your doctor, pharmacist or nurse if you have already had problems after injections, such as dizziness/feeling faint, shortness of breath, swelling or skin rashes.
• A rare neurological adverse effect called reversible posterior encephalopathy syndrome (PRES) has been associated with treatment with Avastin. If you have headache, vision disturbances, confusion or seizures with or without increased pressure, contact your doctor.

Also consult your doctor even if the above has occurred only in the past.
Before starting treatment with Avastin or during treatment with Avastin:

• if you have had or have pain in the mouth, teeth and/or jaw/mandible, or swelling or inflammation in the mouth, or numbness or heaviness in the jaw/mandible, or lose a tooth, immediately report it to your doctor and dentist;
• if you are to undergo invasive dental treatment or dental surgery, tell your dentist that you are being treated with Avastin, especially if you have received or are receiving a bisphosphonate injection into the blood.

Your doctor or dentist may suggest that you have a dental check-up before starting the
treatment with Avastin.

Children and adolescents
Therapy with Avastin is not recommended in children and adolescents under the age of 18 years
as neither safety nor benefits have been established in this patient population.
Bone tissue death (osteonecrosis) in bones other than the jaw has been found in patients
under the age of 18 years treated with Avastin.

Other medicines and Avastin
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might
take any other medicines.
Associations of Avastin with another medicine, called sunitinib malate (prescribed for kidney
and gastrointestinal tumors), can cause serious side effects. Discuss this with your doctor to
ensure you do not combine these drugs.
Tell your doctor if you are using platinum-based or taxane therapies for metastatic lung or
breast cancer. These therapies in combination with Avastin may increase the risk of
serious side effects.
Tell your doctor if you have recently received or are receiving radiotherapy.

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

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

Important information about some ingredients of Avastin
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. essentially
‘sodium-free’.

3. How to use Avastin

Dosage and frequency of administration
The dose of Avastin needed depends on your body weight and the type of cancer that needs 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 appropriate dose for you. Treatment with Avastin will be
administered once every 2 or 3 weeks. The number of infusions you will receive will depend on your
response to treatment; however, you should continue to receive this treatment as long as
Avastin is no longer able to block the growth of your tumor. 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
that will be prescribed for you, a portion of the vial contents or the entire vial of Avastin will be
diluted with a sodium chloride solution before use. The doctor or nurse will administer
this diluted solution of Avastin to you with an intravenous infusion (an IV drip into a vein). The first
infusion will be administered over 90 minutes. If this is well tolerated, the second
infusion may be administered over 60 minutes. Subsequent infusions may be
administered over 30 minutes.

The administration of Avastin must be temporarily interrupted

• if severe high blood pressure problems occur, requiring treatment with medications to control blood pressure,
• if you have problems with wound healing after surgery,
• if you are to undergo surgery.

The administration of Avastin must be permanently interrupted if one of the
following problems occurs

• severe high blood pressure that cannot be controlled with antihypertensive drugs, or a sudden and severe increase in blood pressure,
• protein in the urine associated with edema (swelling of the body),
• perforation of the intestinal wall,
• an abnormal connection or passage between the trachea and esophagus, internal organs and skin, vagina and any section of the gastrointestinal tract, or between other tissues that are not normally connected (fistula), and which are considered severe by the doctor,
• severe infections of the skin or deeper layers under the skin,
• blood clots in the arteries,
• blood clots in the pulmonary blood vessels,
• severe bleeding of any kind.

If an overdose of Avastin is administered

• You may experience a severe migraine. In this case, seek immediate medical attention from your doctor, pharmacist or nurse.

If you forget to take a dose of Avastin

• The doctor will decide the most appropriate time to administer your next dose of Avastin. Discuss this with your doctor.

If you stop treatment with Avastin
Stopping treatment with Avastin may stop the action of containing tumor growth.
Do not stop treatment with Avastin before talking to your doctor.
If you have any doubts about the use of this medicine, ask your doctor, pharmacist or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If you get any side effect, even if not listed in this leaflet, tell 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 member of medical staff immediately. Symptoms may include: difficulty breathing or chest pain. There may also
be redness of the skin or flushing or rash, chills and tremors, feeling unwell (nausea) or vomiting, swelling, dizziness, fast heartbeat and
loss of consciousness.

If you experience any of the side effects described below, seek immediate medical attention.
Serious side effects, which can be very common(may affect more than 1 in

• 10) ,include:
• high blood pressure,
• numbness or tingling in the hands or feet,
• decreased number of blood cells, including white blood cells, which fight infections (this may be accompanied by fever), and cells that help with blood clotting,
• feeling weak and lacking energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Serious side effects, which can be common(may affect up to 1 in 10 people),
include:

• intestinal perforation,
• bleeding, including bleeding in the lungs in patients with non-small cell lung cancer,
• blocked arteries by a blood clot,
• blocked veins by a blood clot,
• blocked pulmonary blood vessels by a blood clot,
• blocked leg veins by a blood clot,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, soreness, pain or blistering on the fingers or toes,
• decreased number of red blood cells,
• lack of energy,
• stomach and intestinal disorders,
• muscle and joint pain, muscle weakness,
• dry mouth associated with thirst and/or decreased or dark urine,
• inflammation of the oral mucosa, intestines, lungs and airways, reproductive and urinary tract,
• ulcers in the mouth and esophagus that can cause pain and difficulty swallowing,
• pain, including headache, back pain and pain in the pelvic area and anus,
• localized abscesses,
• infection, and in particular infection in the blood or bladder,
• reduced blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal blockage,
• changes in urine tests (presence of protein in the urine),
• shortness of breath or reduced oxygen levels in the blood,
• skin or deep tissue infections,
• fistulas: abnormal tubular connection between internal organs and skin or other tissues that are not normally connected to each other, including connections between the vagina and gastrointestinal tract in patients with cervical cancer,
• allergic reactions (symptoms 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 of rarefrequency (may affect up to 1 in 1000 people) include:

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

Serious side effects of unknownfrequency (frequency cannot be estimated on the basis of
available data) include:

• severe skin or deep tissue infections, especially if you have had perforations in the intestinal wall or problems with wound healing,
• a negative effect on women's ability to have children (see sections below the list of side effects for further recommendations),
• a condition of the brain with symptoms such as seizures, headache, confusion and vision changes (reversible posterior encephalopathy syndrome (PRES)),
• symptoms suggesting changes in normal brain function (headache, vision disturbances, confusion or seizures) and high blood pressure,
• dilation and weakening of the wall of a blood vessel or a tear in the wall of a blood vessel (aneurysms and arterial dissections).
• obstruction of a small (i) blood vessel(s) in the kidney,
• an abnormally high pressure in the blood vessels of the lungs that makes the right side of the heart work harder than normal,
• perforation of the cartilage separating the nostrils,
• perforation of the stomach or intestine,
• an open wound or perforation in the lining of the stomach or small intestine (symptoms may include abdominal pain, feeling of fullness, black tarry stools, blood in the stool or blood in the vomit),
• bleeding from the lower part of the large intestine,
• gum injuries, with exposure of jawbone/jawbone that does not heal, which may be associated with pain and inflammation of the surrounding tissue (see sections below the list of side effects for further recommendations),
• perforation of the gallbladder (symptoms and signs may include abdominal pain, fever and nausea/vomiting).

If you experience any of the side effects described below, seek help as soon as possible
Very commonside effects (may affect more than 1 in 10 people) ,which have not been
serious, include:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tearing),
• changes in speech,
• altered sense of taste,
• runny nose,
• dry skin, peeling and inflammation of the skin, change in skin color,
• weight loss,
• nosebleeds.

Commonside effects (may affect up to 1 in 10 people) that have not been serious,
include:

• changes in voice and hoarseness.

Patients over 65 years of age have a higher risk of experiencing the following side effects:

• blood clots in the arteries, which can lead to stroke or heart attack,
• decreased number of white blood cells and cells that help with blood clotting,
• diarrhea,
• feeling unwell,
• headache,
• feeling tired,
• high blood pressure.

Avastin may also cause changes in laboratory test results prescribed by
your doctor. These include: a decrease in the number of white blood cells, especially
neutrophils (a type of white blood cell that helps protect against infections) in the blood, presence of
protein in the urine, decreased potassium, sodium or phosphorus (a mineral) in the blood, increased
blood glucose, increased alkaline phosphatase (an enzyme) in the blood; increased serum creatinine (a protein measured through blood tests to assess how your
kidneys are functioning); decreased hemoglobin (found in red blood cells and carries oxygen), which may be
serious.
Pain in the mouth, teeth and/or jaw, swelling or blisters in the mouth, numbness
or feeling of heaviness in the jaw/jaw or tooth loss. These may be signs
and symptoms of damage to the jawbone/jawbone (osteonecrosis). Tell your doctor and dentist immediately if you experience any of these effects.
Premenopausal women (women who have a menstrual cycle) may experience irregularities in their menstrual
cycles, absence of menstruation and may have negative consequences 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 the treatment of cancer by intravenous injection.
It has not been developed or manufactured for administration by injection into the eye.
Therefore, the use of this route of administration is not authorized. When Avastin is injected
directly into the eye (off-label use), the following side effects may occur:

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

Reporting side effects
If you get any side effect, even if not listed in this leaflet, tell 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 which is stated on the outer packaging and
on the vial label after the abbreviation “Expiry/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.
Infusion solutions must be used immediately after they have been diluted. If
immediate use is not possible, the user shall be responsible for the storage times and
conditions, which should normally not exceed 24 hours at a temperature
between 2°C and 8°C, unless the infusion solutions have been prepared in a
sterile environment. If the dilution has taken place in a sterile environment, Avastin is stable for 30 days at
a temperature between 2°C and 8°C plus an additional 48 hours at a temperature between 2°C and 30°C.
Do not use Avastin if you notice particulate matter or colour changes before administration.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. 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 ingredients are trehalose dihydrate, sodium phosphate (see section 2 ‘Important information about some components of Avastin’), 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 liquid, from colourless to
light brown 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
pack of Avastin contains one vial.

Marketing Authorisation 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, contact the local representative of the marketing
authorisation holder:

België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11

Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799

България
Рош България ЕООД
Тел: +359 2 818 44 44

Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)

Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111

Magyarország
Roche (Magyarország) Kft.
Tel: +36 1 279 4500

Danmark
Roche a/s
Tlf: +45 - 36 39 99 99

Malta
(See Ireland)

Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140

Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050

Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380

Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00

Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100

Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739

España
Roche Farma S.A.
Tel: +34 - 91 324 81 00

Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88

France
Roche
Tél: +33 (0) 1 47 61 40 00

Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00

Hrvatska
Roche d.o.o.
Tel: + 385 1 47 22 333

România
Roche România S.R.L.
Tel: +40 21 206 47 01

Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700

Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00

Ísland
Roche a/s
c/o Icepharma hf
Sími:+354 540 8000

Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201

Italia
Roche S.p.A.
Tel: +39 - 039 2471

Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500

Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76

Sverige
Roche AB
Tel: +46 (0) 8 726 1200

Latvija
Roche Latvija SIA
Tel: +371 - 6 7039831

United Kingdom (Northern Ireland)
Roche Products (Ireland) Ltd.
Tel: +44 (0) 1707 366000

Other sources of information
More detailed information on this medicinal product is available on the website of the European
Medicines Agency: http://www.ema.europa.eu

ANNEX IV
SCIENTIFIC CONCLUSIONS AND JUSTIFICATION FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATIONS
Scientific conclusions
In light of the assessment by the Pharmacovigilance and Risk Assessment Committee
(PRAC) of the Periodic Safety Update Reports (PSURs) for bevacizumab, the scientific
conclusions of the Committee for Medicinal Products for Human Use (CHMP) are as
follows:
Reactions of anaphylactic and anaphylactoid type are included in section 4.8 of the SmPC as
"Hypersensitivity/infusion reactions". However, in light of available data on anaphylactic shock
from the literature and spontaneous reporting cases including a close temporal relationship, a
de-challenge and/or positive re-challenge and considering a plausible mechanism of action, the
PRAC considers that a causal relationship between bevacizumab and anaphylactic shock is at least a
reasonable possibility.
The PRAC concluded that the product information containing bevacizumab should be
modified accordingly .
The CHMP agrees with the scientific conclusions of the PRAC.

Justification for the variation of the terms of the marketing authorisations
Based on the scientific conclusions on bevacizumab, the CHMP considers that the benefit/risk
balance of the medicinal products containing bevacizumab remains unchanged, save for the proposed
changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisations.