ALYMSYS 25 mg/mL concentrate for infusion solution

Introduction

Package Leaflet: Information for the User

Alymsys 25 mg/ml concentrate for solution for infusion

bevacizumab

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 further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Alymsys and what is it used for

The active substance 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), which is located on the walls of blood and lymphatic vessels in the body. The VEGF protein causes blood vessels to grow into the tumor, supplying it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the growth of blood vessels that provide the necessary nutrients and oxygen to the tumor.

Alymsys is a medicine used to treat adult patients with advanced colon or rectal cancer. Alymsys will be given in combination with a chemotherapy treatment that contains a fluoropyrimidine medicine.

Alymsys is also used to treat adult patients with metastatic breast cancer. When used in patients with breast cancer, it will be given with a chemotherapy medicine called paclitaxel or capecitabine.

Alymsys is also used to treat adult patients with advanced non-small cell lung cancer. Alymsys will be given along with a platinum-based chemotherapy regimen.

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

Alymsys is also used to treat adult patients with advanced kidney cancer. When used in patients with kidney cancer, it will be given with another type of medicine called interferon.

Alymsys is also used to treat 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 given 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 at least 6 months after they were last treated with a platinum-based chemotherapy regimen, Alymsys will be given 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 at least 6 months after they were last treated with a platinum-based chemotherapy regimen, Alymsys will be given in combination with topotecan, or pegylated liposomal doxorubicin.

Alymsys is also used to treat adult patients with persistent, recurrent, or metastatic cervical cancer. Alymsys will be given in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum-based treatment.

2. What you need to know before you use Alymsys

Do not use Alymsys

• if you are allergic (hypersensitive) to bevacizumab or 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 other recombinant human or humanized antibodies.
• if you are pregnant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using Alymsys

• It is possible that Alymsys may increase the risk of causing perforations in the wall of the intestine. 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 connection between two organs or sacs. The risk of developing a connection 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 after surgery. If you are going to have surgery, have had major surgery in the last 28 days, or have a surgical wound that has not healed, you should not use this medicine.

• Alymsys may increase the risk of developing serious skin or deep skin layer infections, especially if you have had perforations in the wall of the intestine or problems with wound healing.
• Alymsys may increase the risk of high blood pressure. 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 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 have high blood pressure.

• The risk of developing blood clots or blockages 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 blood clots or blockages in your arteries in the past. Consult your doctor, as blood clots or blockages can cause a heart attack and stroke.

• Alymsys may also increase the risk of developing blood clots or blockages 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 medicines that thin your 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 spitting up blood. Consult your doctor if you have noticed this before.

• Alymsys may increase the risk of your heart becoming weakened. It is essential that you inform your doctor if you have ever been treated with anthracyclines (a specific type of chemotherapy used to treat some types of cancer, such as doxorubicin) or have received radiation therapy in the chest or have heart disease.
• Alymsys may cause infections and decrease the number of neutrophils (a type of blood cell important for protecting you against bacteria).

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

• A rare neurological side effect called posterior reversible encephalopathy syndrome (PRES) has been associated with treatment with Alymsys. If you have a headache, changes in vision, confusion, or seizures with or without high blood pressure, consult your doctor.
• There have been reports of bone tissue death (osteonecrosis) 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 ulcers in the mouth, numbness, or a feeling of heaviness in the jaw, or loss of a tooth. These may be signs and symptoms of bone damage in the jaw (osteonecrosis). Inform your doctor and dentist immediately if you experience any of these.

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:

Before you start 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 side effects may occur:

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

flashes of light with floaters, progressing to a loss of part of the vision,

• Increased eye pressure,
• Bleeding in the eye.

Children and adolescents

Alymsys is not recommended for use in children and adolescents under 18 years old, as the safety and benefit in these patients have not been established.

Other medicines and Alymsys

Tell your doctor, pharmacist, or nurse if you are using, have recently used, or might use any other medicines.

The combination of Alymsys with another medicine called sunitinib malate (prescribed for kidney or gastrointestinal cancer) may cause serious side effects. Consult your doctor to ensure that you do not combine these medicines.

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

Tell 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 prevent the formation of new blood vessels. Your doctor must advise you to use a contraceptive method during treatment with Alymsys and for at least 6 months after the last dose of Alymsys.

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

Do not breastfeed your baby during treatment with Alymsys and for at least 6 months after the last dose of Alymsys, as this medicine 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 who have a menstrual cycle) may notice that their periods become irregular or stop and may experience fertility problems. If you are thinking of having children, you should discuss this with your doctor before starting treatment.

Driving and using machines

Alymsys has not been shown to reduce your ability to drive or use tools or machines. However, somnolence 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 use machines until the symptoms disappear.

Alymsys contains sodium.

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

3. How to use Alymsys

Dose and frequency of administration

The dose of Alymsys needed depends on your weight and the type of cancer being treated. The recommended dose is 5 mg, 7.5 mg, 10 mg, or 15 mg per kilogram of body weight. Your doctor will prescribe the most suitable dose of Alymsys for you, 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 should continue until Alymsys can no longer slow down 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 solution for infusion. Depending on the dose prescribed for you, a fraction or all of the 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 an intravenous infusion (by drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion can be given over 60 minutes. Subsequent infusions can be given over 30 minutes.

Administration of Alymsys should be temporarily interrupted:

The administration of Alymsys should be permanently stopped if you have:

• severe high blood pressure that cannot be controlled with blood pressure medicines; or if there is a sudden and severe increase in blood pressure,
• protein in the urine accompanied by swelling of the body,
• a perforation in the wall of the intestine,
• an abnormal connection between the trachea and esophagus, between internal organs and the skin, between the vagina and any part of the intestine, or between other tissues that are not normally connected (fistula), and your doctor considers it severe,
• severe skin or deep skin layer infections,
• blood clots in the arteries,
• blood clots in the pulmonary blood vessels,
• any severe bleeding.

If you use more Alymsys than you should

• you may have severe migraine. If this happens, you should inform your doctor, pharmacist, or nurse immediately.

If you forget to use Alymsys

• your doctor will decide when you should receive the next dose of Alymsys. You should inform your doctor about the missed dose.

If you stop treatment with Alymsys

Stopping treatment with Alymsys may reduce its effect on tumor growth. Do not stop treatment with Alymsys unless you have discussed it with your doctor.

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

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

Allergic Reactions

If you have an allergic reaction, consult your doctor or healthcare professional immediately. The signs may include: difficulty breathing or chest pain. You may also experience redness or flushing of the skin or rash, chills and tremors, feeling of dizziness (nausea) or feeling of discomfort (vomiting).

You should seek help immediately if you suffer from any of the adverse effects mentioned below.

Severe adverse effects that may be very frequent(may affect more than 1 in 10 patients) include:

• high blood pressure,
• feeling of 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 clot,
• feeling of weakness and lack of energy,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

Severe adverse effects that may be frequent(may affect up to 1 in 10 patients) include:

• perforation of the intestine,
• bleeding, including hemorrhage in the lungs in patients with non-small cell lung cancer,
• blockage of the arteries by embolism,
• blockage of the veins by embolism,
• blockage of the blood vessels in the lungs by embolism,
• blockage of the veins in the legs by embolism,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, sensitivity, pain, or blisters on the fingers or toes,
• decrease in the number of red blood cells,
• lack of energy,
• alterations in the stomach and intestine,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced or dark urine output,
• inflammation of the mucous membrane lining of the mouth and intestine, lungs and airways, reproductive system, and urinary tract,
• sores in the mouth and the tube that goes from the mouth to the stomach, which can be painful and cause difficulty swallowing,
• pain, including headache, back pain, in the pelvis and anal regions,
• localized abscesses,
• infection, and in particular infection in the blood or bladder,
• decrease in blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (protein in the urine),
• difficulty breathing or decrease in oxygen levels in the blood,
• infections of the skin or deeper layers under the skin,
• fistula: abnormal tubular communication between internal organs and the skin or other tissues that are not normally connected, including communications between the vagina and intestine in patients with cervical cancer.

Severe adverse effects of unknown frequency(cannot be estimated from available data) include:

• severe infections of the skin or deeper layers under the skin, especially if you had perforations in the intestinal wall or problems with wound healing,
• allergic reactions (the signs may include difficulty breathing, redness of the face, rash, low or high blood pressure, low oxygen levels in the blood, chest pain, or nausea/vomiting),
• negative effect on a woman's ability to have children (see below for more recommendations),
• brain disease with symptoms such as seizures (attacks), headache, confusion, and vision changes (posterior reversible encephalopathy syndrome or PRES),
• symptoms suggesting changes in normal brain function (headaches, vision changes, confusion, or seizures), and high blood pressure,
• increase and weakening of the wall of a blood vessel or tear of the wall of a blood vessel (aneurysms and arterial dissections).
• obstruction of small blood vessels in the kidney,
• abnormally high blood pressure in the blood vessels of the lungs that makes the right side of the heart work harder than normal,
• perforation in the wall of the cartilage that separates the nasal openings,
• perforation in the stomach or intestine,
• ulcer or perforation in the lining of the stomach or small intestine (these signs may include abdominal pain, feeling of bloating, black stools, stools with blood, or blood in the vomit),
• bleeding from the lower part of the large intestine,
• lesions on the gums, with the jawbone exposed that do not heal and may be associated with pain and inflammation of the surrounding tissues (for more recommendations, see the list of adverse effects below),
• perforation of the gallbladder (the symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you notice any of these adverse effects mentioned, seek medical attention as soon as possible.

Non-severe adverse effects that are very frequent(may affect more than 1 in 10 patients) are:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech alterations,
• taste alterations,
• nasal secretion,
• dry skin, peeling, and inflammation of the skin, changes in skin color,
• weight loss,
• nosebleeds.

Non-severe adverse effects that are frequent(may affect up to 1 in 10 patients) are:

• changes in voice and hoarseness.

Patient over 65 years of age have a higher risk of experiencing the following:

• embolism in the arteries that can cause stroke or heart attack,
• reduction in the number of white blood cells and platelets (that help with blood clotting) in the blood,
• diarrhea,
• discomfort,
• headache,
• fatigue,
• high blood pressure.

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

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is an adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Alymsys

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

Do not use this medicine after the expiration date stated on the packaging and on the label of the vial after EXP. The expiration date is the last day of the month indicated.

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

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

The solution for infusion should be administered immediately after dilution. If it is not administered immediately, the storage times and conditions are the responsibility of the user and would normally not exceed 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 be 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 foreign particles or discoloration before administration.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Alymsys

• The active substance is bevacizumab. Each ml 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 ingredients are trehalose dihydrate, sodium phosphate monobasic monohydrate, disodium phosphate, polysorbate 20, and water for injectable preparations (see section 2 "Alymsys contains sodium").

Appearance and Package Contents of the Product

Alymsys is a concentrate for solution for infusion (sterile concentrate). The concentrate is a colorless to pale brown or yellowish 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 one vial.

Marketing Authorization Holder

Mabxience Research SL

C/ Manuel Pombo Angulo 28 - 3rd and 4th floor

28050 Madrid

Spain

Manufacturer

GH GENHELIX S.A.

León Technology Park

GENHELIX Building

C/ Julia Morros, s/n

Armunia, 24009 León, Spain

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

Date of the Last Revision of this Leaflet:

Other Sources of Information

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu.