Prospecto: information for the user

Alymsys 25 mg/ml concentrate for solution for infusion

bevacizumab

Read this prospect carefully before starting to use this medicine because it contains important information for you.

−Keep this prospect, as you may need to read it again.

−If you have any questions, consult your doctor, pharmacist, or nurse.

−If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they do not appear in this prospect. See section 4.

1.What is Alymsys and what it is used for

2.What you need to know before starting to use Alymsys

3.How to use Alymsys

4.Possible adverse effects

5.Storage of Alymsys

6.Contents of the package and additional information

The active principle of Alymsys is bevacizumab, a humanized monoclonal antibody (a type of protein that is normally produced by the immune system to help the body defend itself against infections and cancer). Bevacizumab selectively binds to a protein called vascular endothelial growth factor (VEGF, English acronym), which is located in the walls of blood and lymphatic vessels of the body. The VEGF protein causes blood vessels to grow within the tumor, which supplies it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels, which provide the necessary nutrients and oxygen for the tumor.

Alymsys is a medication used for the treatment of adult patients with advanced colorectal or rectal cancer. Alymsys will be administered in combination with a chemotherapy regimen containing a fluoropyrimidine medication.

Alymsys is also used for the treatment of adult patients with metastatic breast cancer. When used in patients with breast cancer, it will be administered with a chemotherapy medication called paclitaxel or capecitabine.

Alymsys is also used for the treatment of adult patients with advanced non-small cell lung cancer. Alymsys will be administered along with a platinum-based chemotherapy regimen.

Alymsys is also used for the treatment of adult patients with advanced non-small cell lung cancer when cancer cells have specific mutations in a protein called the epidermal growth factor receptor (EGFR). Alymsys will be administered in combination with erlotinib.

Alymsys is also used for the treatment of adult patients with advanced renal cancer. When used in patients with renal cancer, it will be administered with another type of medication called interferon.

Alymsys is also used for the treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. When used in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, it will be administered in combination with carboplatin and paclitaxel.

When used in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease for at least 6 months since their last treatment 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 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a recurrence of their disease for at least 6 months since their last treatment with a platinum-based chemotherapy regimen, Alymsys will be administered in combination with 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 combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum-based treatment.

No use Alymsys

•If you are allergic (hypersensitive) to bevacizumab or any of the other components of this medication (listed in section 6).

•If you are allergic (hypersensitive) to products derived from Chinese hamster ovary cells (CHO) or other recombinant human or humanized antibodies.

•If you are pregnant.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Alymsys

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

•Alymsys may increase the risk of developing an abnormal communication between two organs or vesicles. The risk of developing communications between the vagina and any part of the intestine may increase if you have persistent, recurrent, or metastatic cervical cancer.

•Alymsys may increase the risk of bleeding or problems with wound healing. If you are to be operated on, have had major surgery in the last 28 days, or have an unhealed surgical wound, do not use this medication.

•Alymsys may increase the risk of developing severe skin infections or deep tissue infections, especially if you had intestinal perforations or wound healing problems.

•Alymsys may increase the risk of hypertension. If you have uncontrolled high blood pressure, consult your doctor, it is essential to ensure that your blood pressure is controlled before starting treatment with Alymsys.

•If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.

•This medication increases the risk of having proteins in the urine, especially if you already have high blood pressure.

•The risk of developing thrombi or clots in your arteries (a type of blood vessel) may increase if you are over 65 years old, if you have diabetes, or if you have had thrombi or clots in your arteries in the past. Consult your doctor, as thrombi or clots can cause heart attack and stroke.

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

•Alymsys may cause bleeding, especially bleeding related to the tumor. Consult your doctor if you have a tendency or family history of bleeding disorders or are taking medications that thin the blood for any reason.

•Alymsys may cause bleeding in and around your brain. Consult your doctor if you have metastatic cancer that affects your brain.

•Alymsys may increase the risk of bleeding in your lungs, including coughing or expectoration of blood. Consult your doctor if you have noticed this previously.

•Alymsys may increase the risk of heart failure. It is essential to inform your doctor if you have ever been treated with anthracyclines (a specific type of chemotherapy used to treat certain types of cancer, such as doxorubicin) or have received radiation therapy in the chest, or if you have a heart disease.

•Alymsys may cause infections and decrease the number of neutrophils (a type of blood cell important for your protection against bacteria).

•Alymsys may cause hypersensitivity and/or reactions after infusion (reactions related to the injection of the medication). Consult your doctor, pharmacist, or nurse if you have previously experienced problems after injections, such as dizziness/dizziness, difficulty breathing, swelling, or skin rash.

•A rare neurological adverse effect called reversible posterior leukoencephalopathy syndrome (RPLS) has been associated with treatment with Alymsys. If you have headaches, vision changes, confusion, or seizures (convulsions) with or without high blood pressure, consult your doctor.

•Cases of bone death (osteonecrosis) have been reported in bones other than the jaw in patients under 18 years old treated with Alymsys. Pain in the mouth, teeth, and/or jaw, swelling, or sores in the mouth, numbness, or feeling of heaviness of the jaw, or tooth loss. These may be signs and symptoms of jaw bone damage (osteonecrosis). Immediately inform your doctor and dentist if you experience any of them.

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

Before starting treatment with Alymsys or during treatment with Alymsys:

•If you have or have had pain in the mouth, teeth, and/or jaw, swelling, or sores in the mouth, numbness, or feeling of heaviness of the jaw, or tooth loss, immediately inform your doctor and dentist.

•If you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Alymsys, particularly when you are also receiving or have received an injection of bisphosphonates in your blood.

Before starting treatment with Alymsys, you may be advised to have a dental check-up.

Alymsys has been developed and manufactured to treat cancer by injection into the bloodstream. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for use in this way. When Alymsys is injected directly into the eye (unapproved use), the following adverse effects may occur:

•Infection or inflammation of the eyeball,

•Redness of the eye, small particles or spots in vision (floaters), eye pain

ocular,

•Light flashes with floaters, progressing to partial loss of vision,

•Increased intraocular pressure,

•Bleeding in the eye.

Children and adolescents

Do not recommend the use of Alymsys in children and adolescents under 18 years old as the safety and benefit have not been established in these patients.

Other medications and Alymsys

Inform your doctor, pharmacist, or nurse if you are using, have used recently, or may need to use any other medication.

The combination of Alymsys with another medication called sunitinib malate (prescribed for renal and gastrointestinal cancer) may cause severe adverse effects. Consult your doctor to ensure that you do not combine these medications.

Consult your doctor if you are receiving platinum-based or taxane-based treatment for metastatic breast or lung cancer. These treatments combined with Alymsys may increase the risk of severe adverse effects.

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

Pregnancy, breastfeeding, and fertility

Do not use Alymsys if you are pregnant. Alymsys may harm the fetus, as it may inhibit the formation of new blood vessels. Your doctor should advise you to use a contraceptive method during treatment with Alymsys and at least 6 months after the last dose of Alymsys.

If you are pregnant, think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before using this medication.

Do not breastfeed your baby during treatment with Alymsys and at least 6 months after the last dose of Alymsys, as this medication may interfere with the growth and development of your baby.

Alymsys may affect female fertility. Consult your doctor for more information.

Pre-menopausal women (women with menstrual cycle) may notice that their periods become irregular or disappear and may experience fertility problems. If you are planning to have children, consult your doctor before starting your treatment.

Driving and operating machines

Alymsys has not been observed to decrease your ability to drive or operate tools or machines. However, drowsiness and fainting have been reported with the use of Alymsys. If you experience symptoms that affect your vision or concentration, or your reaction time, do not drive or operate machines until the symptoms disappear.

Alymsys contains sodium

This medication contains less than 1 mmol of sodium (23 mg) per vial, which is essentially "sodium-free".

Dosage and Administration Frequency

The dosage of Alymsys required depends on your weight and the type of cancer being treated. The recommended dosage is 5 mg, 7.5 mg, 10 mg, or 15 mg per kilogram of body weight. Your doctor will prescribe the most suitable dosage of Alymsys for your case, and you will be treated with Alymsys once every 2 or 3 weeks. The number of infusions you receive will depend on how you respond to treatment and you should continue it until Alymsys can no longer stop tumor growth. Your doctor will discuss these aspects with you.

Form and Route of Administration

Do not shake the vial.

Alymsys is a concentrate for infusion solution. Depending on the dosage prescribed, a fraction or the entire contents of the Alymsys vial will be diluted with sodium chloride solution before administration. A doctor or nurse will administer this diluted Alymsys solution as intravenous infusion (through a drip in your veins). The first infusion will be administered over 90 minutes. If you tolerate this infusion well, the second can be administered over 60 minutes. Subsequent infusions can be administered over 30 minutes.

The administration of Alymsys must be temporarily interrupted:

•if you develop severe hypertension that requires treatment with antihypertensive medications,

•if you have problems with wound healing after surgery,

•if you have undergone surgery.

The administration of Alymsys must be permanently discontinued if you have:

•severe hypertension that cannot be controlled with antihypertensive medications; or in the event of a sudden and severe increase in blood pressure,

•proteinuria accompanied by body swelling,

•intestinal perforation,

•an abnormal communication of a tubular or fistulous type between the trachea and esophagus (the passage to the stomach), between internal organs and the skin, between the vagina and any part of the intestine or between other tissues that are normally not connected (fistula), and which your doctor considers severe,

•severe skin or deep skin layer infections,

•arterial embolism (blood clot),

•pulmonary vein embolism,

•any severe bleeding.

If you use more Alymsys than you should

•you may experience severe migraine. If this occurs, you must inform your doctor, pharmacist, or nurse immediately.

If you forget to use Alymsys

•Your doctor will decide when the next dose of Alymsys should be administered. You must inform your doctor of this oversight.

If you interrupt treatment with Alymsys

The interruption of treatment with Alymsys may suppress its effect on tumor growth. Do not interrupt treatment with Alymsys unless you have consulted with your doctor.

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

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

Allergic reactions

If you have an allergic reaction, consult your doctor or healthcare professional immediately. Symptoms may include: difficulty breathing or chest pain. You may also experience skin redness or flushing, rash, chills, and tremors, nausea or vomiting.

You must seek immediate help if you experience any of the following side effects.

Severe side effects that may bevery common(may affect more than 1 in 10 patients) include:

•high blood pressure,

•numbness or tingling in hands or feet,

•decrease in the number of blood cells, including white blood cells that help fight infections (this may be accompanied by fever), and platelets that help blood to clot,

•feeling weak and lacking energy,

•fatigue,

•diarrhea, nausea, vomiting, and abdominal pain.

Severe side effects that may becommon(may affect up to 1 in 10 patients) include:

•intestinal perforation,

•bleeding, including hemoptysis in patients with non-microcytic lung cancer,

•embolism of arteries,

•embolism of veins,

•embolism of pulmonary vessels,

•embolism of leg veins,

•heart failure,

•wound healing problems after surgery,

•redness, peeling, sensitivity, pain, or blisters on fingers or feet,

•decrease in the number of red blood cells,

•lack of energy,

•gastrointestinal and intestinal alterations,

•muscle and joint pain, muscle weakness,

•xerostomia combined with thirst and/or reduced urine output or dark urine,

•inflammation of the mucous membrane of the mouth, intestines, lungs, and airways, reproductive system, and urinary tract,

•mouth and esophageal ulcers that may be painful and cause difficulty swallowing,

•pain, including headache, back pain, pelvic pain, and anal pain,

•localized pus foci,

•infection, and particularly blood or urinary tract infection,

•decrease in cerebral blood flow or stroke,

•drowsiness,

•nasal bleeding,

•increased heart rate,

•intestinal obstruction,

•abnormal urine test (protein in urine),

•difficulty breathing or decreased oxygen levels in blood,

•skin or deeper tissue infections,

•fistula: abnormal communication of a tubular type between internal organs and the skin or other tissues that are normally not connected, including communication between the vagina and intestine in patients with cervical cancer.

Severe side effects ofunknown frequency(cannot be estimated from available data) include:

•serious skin or deeper tissue infections, especially if you had intestinal perforations or wound healing problems,

•allergic reactions (symptoms may include difficulty breathing, facial redness, skin rash, low blood pressure, low oxygen levels in blood, chest pain, or nausea/vomiting),

•negative effect on the woman's ability to have children (see below for more recommendations),

•encephalopathy with symptoms such as seizures, headache, confusion, and visual disturbances (reversible posterior leukoencephalopathy syndrome or RPLS),

•symptoms suggesting changes in normal brain function (headache, visual disturbances, confusion, or seizures), and high blood pressure,

•aneurysm or arterial dissection.

•obstruction of small blood vessels in the kidney,

•abnormally high blood pressure in pulmonary vessels that makes the right side of the heart work harder than normal,

•perforation in the cartilage wall that separates the nasal passages,

•perforation in the stomach or intestine,

•ulcer or perforation in the stomach or small intestine lining (these symptoms may include abdominal pain, feeling bloated, black stools, stools with blood, or blood in vomit),

•lower intestinal bleeding,

•gum lesions, with exposed jawbone that do not heal and may be associated with pain and inflammation of surrounding tissues (see below for more recommendations),

•gallbladder perforation (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you experience any of these side effects mentioned, seek medical attention as soon as possible.

Side effectsvery common(may affect more than 1 in 10 patients) that were not severe are:

•constipation,

•loss of appetite,

•fever,

•eye problems (including increased tear production),

•speech problems,

•taste alterations,

•nasal secretion,

•dry skin, peeling, and inflammation of the skin, skin color changes,

•weight loss,

•nasal bleeding.

Side effectscommon(may affect up to 1 in 10 patients) that were not severe are:

•voice changes and hoarseness.

Patients over 65 years old have a higher risk of experiencing the following:

•embolism in arteries that may cause stroke or heart attack,

•decrease in white blood cells and platelets (which help to clot) in blood,

•diarrhea,

•uncomfortable feeling,

•headache,

•fatigue,

•high blood pressure.

Alymsys may also cause changes in laboratory tests that your doctor will perform. These changes may include a decrease in white blood cells, particularly neutrophils (a type of white blood cell that helps to protect against infections), presence of protein in urine, decrease in potassium, sodium, or phosphorus in blood, increase in blood sugar, increase in alkaline phosphatase (an enzyme) in blood, decrease in hemoglobin (which is found in red blood cells and transports oxygen), which may be severe.

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging and on the vial label after CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C). Do not freeze.

Store the vial in the outer packaging to protect it from light.

The infusion solution must be administered immediately after dilution. If it is not administered immediately, the storage times and conditions in use are the responsibility of the user and are normally not more than 24 hours between 2°C and 8°C, unless the infusion solutions have been prepared in a sterile environment. When dilution takes place in a sterile environment, Alymsys will remain stable after dilution for a period of up to 30 days stored between 2°C and 8°C and for a period of up to 48 hours at temperatures not exceeding 30°C.

Do not use Alymsys if you observe any foreign particles or discoloration before administration.

Medications should not be disposed of through drains or trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Composition of Alymsys

•The active principle is bevacizumab. Each milliliter of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 or 16.5 mg/ml when diluted as recommended.

Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.

Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.

•The other components are trehalose dihydrate, sodium phosphate monobasic monohydrate, disodium phosphate, polisorbate 20, and water for injection (see section 2 "Alymsys contains sodium").

Appearance of the product and contents of the package

Alymsys is a concentrate for solution for infusion (sterile concentrate). The concentrate is a colorless to brown or pale yellow liquid with opalescence contained in a glass vial 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 package of Alymsys contains a vial.

Marketing authorization holder

Mabxience Research SL

C/ Manuel Pombo Angulo 28 - 3a and 4th Floor

28050 Madrid

Spain

Responsible for manufacturing

GH GENHELIX S.A.

Parque Tecnológico de León

Edificio GENHELIX

C/ Julia Morros, s/n

Armunia, 24009 León, Spain

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Last review date of this leaflet:

Other sources of information

The detailed information about this medication is available on the website of the European Medicines Agency:http://www.ema.europa.eu.