ALYMSYS 25 mg /Ml Concentrate For Infusion Solution

Зміст інструкції

1. Alymsys 25 mg/ml concentrate for solution for infusion
   1. What is Alymsys and what is it used for
   2. What you need to know before using Alymsys
   3. How to use Alymsys
   4. Possible side effects
   5. How to store Alymsys
   6. Contents of the pack and other information

Alymsys 25 mg/ml concentrate for solution for infusion

bevacizumab

Medicinal product subject to additional monitoring. This will allow the rapid identification of
new safety information. You can contribute by reporting any adverse effects
experienced during the use of this medicine. See the end of section 4 for
information on how to report adverse effects.

Read this leaflet carefully before you use 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 you experience any side effects, even those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4

Contents of this leaflet:

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

1. What is Alymsys and what is it used for

Alymsys contains the active ingredient 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 tumors). 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 inhibited by blocking the development of the blood
vessels that supply nutrients and oxygen to the tumor.
Alymsys is a medicine used for the treatment of adult patients with advanced
colorectal cancer, i.e. of the colon or rectum. Alymsys will be administered in combination with a
fluoropyrimidine-based chemotherapeutic treatment.
Alymsys is also used for the treatment of adult patients with metastatic breast cancer. In patients with this type of tumor, Alymsys will be administered with a
paclitaxel- or capecitabine-based chemotherapy regimen.
Alymsys is also used for the treatment of adult patients with advanced non-small cell lung cancer. Alymsys will be administered together with a platinum-based chemotherapy regimen.
Alymsys 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). Alymsys will be administered in
association with erlotinib.
Alymsys is also used for the treatment of adult patients with advanced kidney cancer.
In patients with this type of tumor, Alymsys will be administered with another type of medicine
called interferon.
Alymsys is also used for the treatment of adult patients with epithelial ovarian cancer,
fallopian tube cancer or primary peritoneal cancer in advanced stage. In patients
with these types of tumors, Alymsys will be administered in association with carboplatin and paclitaxel.
If used in adult 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 association with carboplatin and gemcitabine or with
carboplatin and paclitaxel.
If used in adult patients with epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in advanced stage whose disease has recurred within
6 months of the last time they were treated with a platinum-based chemotherapy regimen, Alymsys will be administered in association with paclitaxel, topotecan or pegylated liposomal doxorubicin.
Alymsys is also used for the treatment of adult patients with persistent, recurrent or metastatic cervical cancer. Alymsys 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 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 humanized or human 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 perforations in the intestinal wall. If you have conditions that cause inflammation in the abdomen (e.g. diverticulitis, gastric ulcers, chemotherapy-associated colitis), talk to your doctor.
• Alymsys 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.
• Alymsys 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.
• Alymsys may increase the incidence of high blood pressure. If you suffer from high blood pressure that is not well controlled with appropriate medications, discuss this with your doctor. It

is important to ensure that your blood pressure is under control before starting treatment with Alymsys.

• 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 your 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, or if you have previously had blood clots in the arteries. Talk to your doctor because blood clots can lead to heart attacks and strokes.
• Alymsys 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.
• Alymsys can cause bleeding in the brain and around the brain. Consult your doctor if you have a metastatic tumor that affects the brain.
• It is possible that Alymsys increases the risk of bleeding in the lungs, including blood in your cough or saliva. Discuss this with your doctor if you have noticed these events in the past.
• Alymsys may increase the risk of developing heart failure. It is important that your doctor knows if you have previously undergone therapy with anthracyclines (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).
• It is possible that Alymsys causes 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 Alymsys. If you have headache, vision disturbances, confusion or seizures with or without high blood pressure, contact your doctor.
• Death of bone tissue (osteonecrosis) in bones other than the jaw has been observed in patients under the age of 18 treated with Alymsys. Pain in the mouth, teeth and/or jaw, swelling or blisters in the mouth, numbness or feeling of heaviness in the jaw/mandible, or tooth loss may be signs and symptoms of damage to the jaw bones (osteonecrosis). Immediately inform your doctor and dentist if any of these events occur.

Also tell your doctor if the above has occurred in the past.
Before starting treatment with Alymsys or during treatment with Alymsys:

• if you have had or have pain in the mouth, teeth and/or jaw, or swelling or inflammation in the mouth, or numbness or feeling of heaviness in the jaw, or lose a tooth, report it immediately 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 Alymsys, especially if you have received or are receiving a bisphosphonate injection into your blood.

Your doctor or dentist may suggest that you have a dental check-up before starting treatment with Alymsys.
Alymsys 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 Alymsys is injected
directly into the eye (off-label use), the following adverse effects may occur:
indesiderati:

• 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,
• bleeding of the eye.

Children and adolescents
Therapy with Alymsys is not recommended in children and adolescents under the age of 18
as safety and efficacy have not been established in this patient population.

Other medicines and Alymsys
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or may
take any other medicines.
Combinations of Alymsys with another medicine called sunitinib malate (prescribed for kidney and
gastrointestinal tumors) may cause serious side effects. Talk to your doctor to make sure
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 Alymsys may increase the risk of
serious side effects.
Tell your doctor if you have recently received or are receiving radiotherapy.

Pregnancy, breastfeeding and fertility
Do not use this medicine if you are pregnant. Alymsys may harm the unborn
baby as it may interrupt the formation of new blood vessels. Your doctor will
advise you to use adequate contraceptive measures during therapy with Alymsys and for at least
6 months after taking the last dose of Alymsys.
If you are pregnant, suspect or are planning a pregnancy, ask your doctor
or pharmacist for advice before taking this medicine.
Do not breastfeed your baby during treatment with Alymsys and for at least
6 months after taking the last dose of the drug, as Alymsys may interfere with the growth
and development of the baby.
Alymsys may reduce female fertility. Consult your doctor for more information.
Premenopausal women (women who have a menstrual cycle) may experience irregularities in their cycles
menstrual, absence of menstruation and may have negative consequences on fertility. If you are
considering getting pregnant, you should discuss this with your doctor before starting treatment.

Driving and using machines
Alymsys 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 Alymsys. If you experience symptoms that
affect your vision or concentration, or your ability to react, do not drive vehicles and do not use
machinery until the symptoms disappear.

Alymsys contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. it is essentially
“sodium-free”.

3. How to use Alymsys

Dosage and frequency of administration
The dose of Alymsys 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 Alymsys at the appropriate dose for you. Treatment with Alymsys 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 until Alymsys 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. Alymsys is a concentrate for infusion solution. Depending on the dose
prescribed to you, a portion of the vial’s contents or the entire vial of Alymsys
will be diluted with a sodium chloride solution before use. The doctor or nurse will
administer this diluted solution of Alymsys with an intravenous infusion (an IV drip in
a vein). The first infusion will be administered over 90 minutes. If the first infusion is well
tolerated, the second can be administered in 60 minutes. Subsequent infusions may be
administered over 30 minutes.

The administration of Alymsys 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 Alymsys 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, between internal organs and skin, between the 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 you take more Alymsys than you should

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

If a dose of Alymsys is missed

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

Discuss this with your doctor.

If you stop taking Alymsys
Stopping treatment with Alymsys may cause the containment of tumor growth to cease.
Do not stop treatment with Alymsys before talking to your doctor.
If you have any questions 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 will experience them.
The side effects listed below have been observed in patients treated with Alymsys associated with
chemotherapy. This does not mean that these side effects were necessarily caused by Alymsys.

Allergic reactions
If you should experience an allergic reaction, tell your doctor or a member of the medical staff
immediately. The signs may include difficulty breathing or chest pain. Redness of the skin or flushing or
rash, chills and tremors, feeling unwell (nausea) or sick (vomiting), swelling, dizziness, rapid
heartbeat and loss of consciousness may also occur.

If you should experience any of the side effects described below, seek immediate help.
Serious side effects, which 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,
• decreased number of blood cells, including white blood cells, which fight infections (this may be
  accompanied by fever), and cells that contribute to blood clotting,
• feeling of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Serious side effects, which may 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,
• arteries blocked by a blood clot,
• veins blocked by a blood clot,
• pulmonary blood vessels blocked by a blood clot,
• leg veins blocked 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, intestine, 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 and anal area,
• localized abscesses,
• infection, and in particular blood or bladder infection,
• reduced blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (palpitations),
• bowel obstruction,
• alteration of urine tests (presence of protein in the urine),
• shortness of breath or reduced oxygen levels in the blood,
• skin or deep skin layer infections,
• fistulas: abnormal tubular connection between internal organs and skin or other tissues that are not
  normally connected to each other, including connections between 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 blood oxygen levels, chest pain, or nausea/vomiting), Serious side effects of rare
  frequency (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 unknown frequency(frequency cannot be estimated based on available
data) include:

• severe skin or deep skin layer 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 visual disturbances
  (reversible posterior encephalopathy syndrome, PRES),
• symptoms suggesting changes in normal brain function (headache, visual 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),
• blockage of one or more small blood vessels in the kidney,
• abnormally high blood pressure in the vessels of the lungs that makes the right side of the heart work harder
  than normal,
• perforation of the cartilage wall separating the nostrils,
• perforation of the wall of the stomach or intestine,
• an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal
  pain, feeling of bloating, tarry black stools, blood in the stool, or blood in the vomit),
• bleeding from the lower large intestine,
• gum injuries, with exposure of a jaw/maxilla bone 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 should experience any of the side effects described below, seek help as soon as
possible.
Very common side 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.

Common side effects(may affect up to 1 in 10 people), which have not been serious, include:

• changes in voice and hoarseness.

Patients over 65 years of age have a greater 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 contribute to blood clotting,
• diarrhea,
• feeling unwell,
• headache,
• feeling tired,
• high blood pressure.

Alymsys can also cause changes in the results of laboratory tests 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, the presence of protein in the urine, decreased potassium, sodium
or phosphorus (a mineral) in the blood, increased blood sugar, 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
severe.

Reporting of side effects
If you get any side effects, 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 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 vial label 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 must 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 between
2°C-8°C, unless the infusion solutions have been prepared in a sterile environment.
When the dilution has taken place in a sterile environment, Alymsys is stable for a period of up to
30 days at a temperature between 2°C-8°C after dilution and for a period of up to 48 hours at
temperatures not exceeding 30°C.
Do not use Alymsys if you notice particulate matter or colour changes before administration.
Do not dispose of any medicine in waste water or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack 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 monosodium phosphate monohydrate, disodium phosphate, polysorbate 20 and water for injections (see section 2 “Alymsys contains sodium”).

Description of the appearance of Alymsys and contents of the pack
Alymsys is a concentrate for infusion solution (sterile concentrate). The concentrate is an opalescent liquid
from colourless to yellowish or 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 Alymsys contains one vial.

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

Manufacturer
GH GENHELIX S.A.
Parque Tecnológico de León
Edifício GENHELIX
C/Julia Morros, s/n
Armunia, 24009 León, Spain
For further information on this medicinal product, contact the local representative of the marketing
authorisation holder.

België/Belgique/Belgien
Mabxience Research SL
Tél/Tel: +34 917 711 500

Lietuva
Zentiva, k.s.
Tel: +370 52152025

България
Zentiva, k.s.
Teл.: +35924417136

Luxembourg/Luxemburg
Mabxience Research SL
Tél/Tel: +34 917 711 500

Česká republika
Zentiva, k.s.
Tel: +420 267 241 111

Magyarország
Zentiva Pharma Kft.
Tel.: +36 1 299 1058

Danmark
Medical Valley Invest AB
Tlf: +46 40 122131

Malta
Zentiva, k.s.
Tel: +356 2034 1796

Deutschland
Zentiva Pharma GmbH
Tel: +49 (0) 800 53 53 010

Nederland
Medical Valley Invest AB
Tel.: +46 40 122131

Eesti
Zentiva, k.s.
Tel: +372 52 70308

Norge
Medical Valley Invest AB
Tlf: +46 40 122131

Ελλάδα
Win Medica S.A.
Τηλ: +30 210 7488 821

Österreich
G.L. Pharma GmbH
Tel: +43 3136 82577

España
Cipla Europe NV sucursal en España
Tel: +34 91 534 16 73

Polska
Zentiva Polska Sp. z o.o.
Tel: +48 22 375 92 00

France
Zentiva France
Tél: +33 (0) 800 089 219

Portugal
Zentiva Portugal, Lda
Tel: +351210601360

Hrvatska
Zentiva d.o.o.
Tel: +385 1 6641 830

România
ZENTIVA S.A.
Tel: +4 021 304 7597

Ireland
Zentiva, k.s.
Tel: +353 818 882 243

Slovenija
Zentiva, k.s.
Tel: +386 360 00 408

Ísland
Alvogen ehf.
Sími: +354 522 2900

Slovenská republika
Zentiva, a.s.
Tel: +421 2 3918 3010

Italia
Zentiva Italia S.r.l.
Tel: +39 800081631

Suomi/Finland
Medical Valley Invest AB
Puh/Tel: +46 40 122131

Κύπρος
Win Medica S.A.
Τηλ: +30 210 7488 821

Sverige
Medical Valley Invest AB
Tel: +46 40 122131

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

United Kingdom (Northern Ireland)
Zentiva, k.s.
Tel: +44 (0) 800 090 2408

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