Package leaflet: Information for the user

Alymsys 25 mg/ml concentrate for solution for infusion

bevacizumab
Please read all of this leaflet carefully before you start 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 possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

What Alymsys is and what it is used for
What you need to know before you use Alymsys
How to use Alymsys
Possible side effects
How to store Alymsys
Contents of the pack and other information

1. What Alymsys is and what it is used for

Alymsys 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 human vascular endothelial growth factor
(VEGF), which is present on the lining of blood and lymphatic vessels in the body. The VEGF protein
promotes the growth of blood vessels within tumours; 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.
Alymsys is a medicine used to treat adult patients with advanced colorectal cancer, i.e. cancer of the
colon or rectum. Alymsys will be administered in combination with a fluoropyrimidine-based
chemotherapy regimen.
Alymsys is also used to treat adult patients with metastatic breast cancer. In patients with this type of
cancer, Alymsys will be administered together with a chemotherapy regimen based on paclitaxel or
capecitabine.
Alymsys is also used to treat adult patients with advanced non-small cell lung cancer. Alymsys will be
administered together with a platinum-based chemotherapy regimen.
Alymsys 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). Alymsys will
be administered in combination with erlotinib.
Alymsys is furthermore used to treat adult patients with advanced renal cell carcinoma (kidney
cancer). In patients with this type of tumour, Alymsys will be administered in combination with another
type of medicine called interferon.
Alymsys is also used to treat adult female patients with advanced epithelial ovarian cancer, fallopian
tube cancer, or primary peritoneal cancer. In patients with these types of tumours, Alymsys will be
administered in combination with carboplatin and paclitaxel.
When used in adult female patients with epithelial ovarian cancer, fallopian tube cancer, or primary
peritoneal cancer in advanced stage whose disease has recurred at least 6 months after the last time
they were treated with a platinum-based chemotherapy regimen, Alymsys will be administered in
combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.
When used in adult female patients with epithelial ovarian cancer, fallopian tube cancer, or primary
peritoneal cancer in advanced stage whose disease has recurred within 6 months after the last time
they were treated with a platinum-based chemotherapy regimen, Alymsys will be administered in
combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.
Alymsys is also used to treat adult female patients with persistent, recurrent, or metastatic cervical
cancer. Alymsys 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 Alymsys

Do not use Alymsys:

if you are allergic to bevacizumab or to any of the other ingredients of this medicine (listed in section 6).
if you are allergic 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 Alymsys:

Alymsys may increase the risk of developing intestinal wall perforations. If you have conditions causing abdominal inflammation (e.g., diverticulitis, stomach ulcer, chemotherapy-associated colitis), discuss this with your doctor.
Alymsys may increase the risk of developing abnormal connections or passages between two organs or blood vessels. Persistent, recurrent, or metastatic cervical cancer may increase the risk of developing connections between the vagina and any section of the intestine.
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.
Alymsys may increase the risk of developing severe skin infections or infections of deeper tissue layers beneath the skin, especially if you have intestinal wall perforations or impaired wound healing.
This medicine 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 Alymsys.
If you have or have had an aneurysm (a weakened and dilated blood vessel wall) or a tear in a blood vessel wall.
This medicine increases the risk of protein in the urine, particularly 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 previously had arterial blood clots. Discuss this with your doctor, as blood clots can lead to heart attacks and strokes.
Alymsys may also increase the risk of developing blood clots in veins (a type of blood vessel).
This medicine can 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 anticoagulant medications for any reason.
Alymsys can cause bleeding in or around the brain. Consult your doctor if you have metastatic cancer affecting the brain.
Alymsys 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.
Alymsys 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).
Alymsys 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 posterior reversible encephalopathy syndrome (PRES) has been associated with treatment with Alymsys. If you experience headache, visual disturbances, confusion, or seizures with or without high blood pressure, contact your doctor.
In patients under 18 years of age treated with Alymsys, bone tissue death (osteonecrosis) has been observed in bones other than the jaw. Pain in the mouth, teeth, and/or jaw, swelling or blisters in the mouth, numbness or heaviness in the jaw, or tooth loss may be signs and symptoms of jawbone damage (osteonecrosis). Inform your doctor and dentist immediately if any of these events occur.

Talk to your doctor even if any of the above conditions occurred only in the past.
Before starting or during treatment with Alymsys:

if you have had or currently have mouth, teeth, and/or jaw pain, swelling or inflammation in the mouth, numbness or heaviness in the jaw, or tooth loss, report this immediately to your doctor and dentist.
if you need invasive dental treatment or dental surgery, inform your dentist that you are receiving Alymsys, especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting treatment with Alymsys.
Alymsys 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 authorized. When Alymsys is injected directly into the eye (off-label use), the following adverse effects may occur:

infection or inflammation of the eyeball,
eye redness, appearance of particles or moving bodies in the visual field ("floaters"), eye pain,
flashes of light with "floaters" progressing to partial vision loss,
increased eye pressure,
eye bleeding.

Children and adolescents
Treatment with Alymsys is not recommended in children and adolescents under 18 years of age, as neither safety nor efficacy has been established in this patient population.
Other medicines and Alymsys
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
Combining Alymsys with another medicine called sunitinib malate (prescribed for kidney and gastrointestinal cancer) may cause serious adverse effects. Talk to your doctor to ensure you do not combine these medicines.
Inform your doctor if you are receiving platinum-based or taxane therapies for metastatic lung or breast cancer. These therapies in combination with Alymsys may increase the risk of serious adverse effects.
Inform your doctor if you have recently received or are currently receiving radiotherapy.
Pregnancy, breastfeeding, and fertility
You must not use this medicine if you are pregnant. Alymsys can harm the unborn child as it may interfere with the formation of new blood vessels. Your doctor will advise you to use adequate contraception during treatment with Alymsys and for at least 6 months after the last dose of Alymsys.
If you are pregnant, suspect you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
You must not breastfeed during treatment with Alymsys and for at least 6 months after the last dose of the medicine, as Alymsys may interfere with the infant's growth and development.
Alymsys may impair female fertility. Consult your doctor for further information.
Premenopausal women (women who have menstrual cycles) may experience menstrual irregularities or absence of menstruation, which may have negative consequences on fertility. If you are considering having children, discuss this with your doctor before starting treatment.
Driving and using machines
Alymsys has not been shown to reduce the ability to drive or operate tools or machinery.
However, drowsiness and fainting have been reported with the use of Alymsys. If you experience symptoms affecting your vision, concentration, or reaction ability, do not drive or use machinery until symptoms resolve.
Alymsys contains sodium and polysorbate 20
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e., it is essentially "sodium-free".
This medicine contains 1.6 mg of polysorbate 20 per 100 mg/4 ml vial and 6.4 mg per 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 Alymsys

Dose and frequency of administration
The dose of Alymsys you require depends on your body weight and the type of cancer 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 Alymsys at the appropriate dose for you. Treatment with Alymsys 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 Alymsys 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. Alymsys is a concentrate for solution for infusion. Depending on the prescribed dose, part or all of the contents of the Alymsys vial will be diluted with a sodium chloride solution before use. Your doctor or nurse will administer this diluted Alymsys solution as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If the first infusion is well tolerated, the second infusion may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Alymsys administration must be temporarily interrupted

if severe high blood pressure problems occur requiring treatment with medicines to control blood pressure,
if you experience impaired wound healing after surgery,
if you are scheduled to undergo surgery.

Alymsys administration must be permanently discontinued if any of the following 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 trachea and oesophagus, between internal organs and skin, between vagina and any part of the gastrointestinal tract, or between other tissues not normally connected (fistula), considered by the doctor as severe,
severe skin infections or deep infections beneath the skin,
blood clots in the arteries,
blood clots in the pulmonary blood vessels,
severe bleeding of any type.

If you receive more Alymsys than you should

you may experience severe headache. In this case, contact your doctor, pharmacist, or nurse immediately.

If a dose of Alymsys is missed

your doctor will decide the most appropriate time to administer the next dose of Alymsys.

Discuss this with your doctor.
If you stop treatment with Alymsys
Stopping treatment with Alymsys may cause the tumour growth control effect to cease. Do not stop treatment with Alymsys without first discussing it with your doctor.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects listed below have been observed in patients treated with Alymsys in combination with chemotherapy. This does not mean that these side effects were necessarily caused by Alymsys.

Allergic reactions
If you experience an allergic reaction, inform your doctor or a healthcare professional immediately. Signs may include difficulty breathing or chest pain. Other symptoms may include skin redness, hot flushes or rash, chills and tremors, feeling unwell (nausea) or malaise (vomiting), swelling, mild confusion, 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,
sensation of numbness or tingling in the hands or feet,
reduction in blood cell counts, including white blood cells, which help 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 haemorrhage in patients with non-small cell lung cancer,
blocked arteries due to blood clots,
blocked veins due to blood clots,
blood vessels in the lungs blocked by blood clots,
leg veins blocked by blood clots,
heart failure,
problems with wound healing after surgery,
redness, peeling, tenderness, pain, or blistering on the palms of the hands or soles of the feet,
reduced 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 reduced or dark urine,
inflammation of the mucous membranes of the mouth, intestine, lungs and airways, and of the reproductive and urinary tracts,
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 supply to the brain or stroke,
drowsiness,
nosebleeds,
increased heart rate (palpitations),
intestinal obstruction,
abnormal urine tests (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 with rare frequency (may affect up to 1 in 1,000 people) include:

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

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

severe skin infections or infections of deeper layers under the skin, especially if you have had intestinal wall perforations or problems with wound healing,
a negative effect on women's fertility (see the paragraphs 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 or 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 blood vessel wall (aneurysms and arterial dissections),
blockage of one or more small blood vessels in the kidney,
abnormally high blood pressure in the blood vessels of the lungs, making the right side of the heart work harder than normal,
perforation of the cartilage wall separating the nostrils,
perforation of the stomach or intestinal wall,
an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, sensation of abdominal bloating, 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 bone in the jaw/mandible that does not heal, which may be associated with pain and inflammation of surrounding tissue (see the paragraphs following the list of side effects for further recommendations),
gallbladder perforation (symptoms and signs 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.

Very common non-serious side effects (may affect more than 1 in 10 people) include:

constipation,
loss of appetite,
fever,
eye problems (including increased tearing),
speech disturbances,
altered sense of taste,
runny nose,
dry, peeling, and inflamed skin, skin colour changes,
loss of body weight,
nosebleeds.

Common non-serious side effects (may affect up to 1 in 10 people) include:

voice changes and hoarseness.

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

blood clots in the arteries, which may lead to stroke or heart attack,
reduction in white blood cell count and in cells involved in blood clotting,
diarrhoea,
feeling unwell,
headache,
fatigue,
high blood pressure.

Alymsys may also cause changes in laboratory test results prescribed by your doctor. These include: a reduction in white blood cell count, 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.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via 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 Alymsys

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 label of the vial after “EXP”. The expiry date refers to the last day of that 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 should be used immediately after dilution. If not used immediately, the storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at a temperature of 2°C–8°C, unless the infusion solutions have been prepared under sterile conditions.
When dilution has been carried out under sterile conditions, Alymsys is stable for up to 30 days at a temperature of 2°C–8°C after dilution and for up to 48 hours at temperatures not exceeding 30°C.
Do not use Alymsys if you notice particulate matter or changes in colour before administration.
Do not dispose of any medicine 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 Alymsys 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, monobasic monohydrate sodium phosphate, dibasic sodium phosphate, polysorbate 20 (E 432) and water for injections (see section 2 “Alymsys contains sodium and polysorbate 20”).

Description of the appearance of Alymsys and contents of the pack
Alymsys is a concentrate for solution for infusion (sterile concentrate). The concentrate is a sterile, opalescent liquid, colourless to yellowish or light brown, in a glass vial sealed 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 pack of Alymsys contains one vial.

Marketing Authorization Holder
Mabxience Research SL
C/ Manuel Pombo Angulo 28
28050 Madrid
Spain

Manufacturer
GH GENHELIX S.A.
Parque Tecnológico de León
Edificio GENHELIX
C/Julia Morros, s/n
Armunia, 24009 León, Spain

For further information about this medicine, please contact the local representative of the Marketing Authorization Holder.

België/Belgique/Belgien Lietuva
Mabxience Research SL Zentiva, k.s.
Tél/Tel: +34 917 711 500 Tel: +370 52152025

България Luxembourg/Luxemburg
Zentiva, k.s. Mabxience Research SL
Teл.: +35924417136 Tél/Tel: +34 917 711 500

Česká republika Magyarország
Zentiva, k.s. Zentiva Pharma Kft.
Tel: +420 267 241 111 Tel.: +36 1 299 1058

Danmark Malta
Medical Valley Invest AB Zentiva, k.s.
Tlf: +46 40 122131 Tel: +356 2034 1796

Deutschland Nederland
Zentiva Pharma GmbH Medical Valley Invest AB
Tel: +49 (0) 800 53 53 010 Tel.: +46 40 122131

Eesti Norge
Zentiva, k.s. Medical Valley Invest AB
Tel: +372 52 70308 Tlf: +46 40 122131

Ελλάδα Österreich
Win Medica S.A. G.L. Pharma GmbH
Τηλ: +30 210 7488 821 Tel: +43 3136 82577

España Polska
Cipla Europe NV sucursal en España Zentiva Polska Sp. z o.o.
Tel: +34 91 534 16 73 Tel: +48 22 375 92 00

France Portugal
Zentiva France Zentiva Portugal, Lda
Tél: +33 (0) 800 089 219 Tel: +351210601360

Hrvatska România
Zentiva d.o.o. ZENTIVA S.A.
Tel: +385 1 6641 830 Tel: +4 021 304 7597

Ireland Slovenija
Zentiva, k.s. Zentiva, k.s.
Tel: +353 818 882 243 Tel: +386 360 00 408

Ísland Slovenská republika
Alvogen ehf. Zentiva, a.s.
Sími: +354 522 2900 Tel: +421 2 3918 3010

Italia Suomi/Finland
Zentiva Italia S.r.l. Medical Valley Invest AB
Tel: +39 800081631 Puh/Tel: +46 40 122131

Κύπρος Sverige
Win Medica S.A. Medical Valley Invest AB
Τηλ: +30 210 7488 821 Tel: +46 40 122131

Latvija
Zentiva, k.s.
Tel: +371 67893939

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