Alymsys 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Alymsys 25 mg/ml concentrate for solution for infusion

bevacizumab

Read the entire leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you experience any side effects, talk to your doctor, pharmacist or nurse, even if it is a side effect not listed in this leaflet. See section 4.

Leaflet contents

1. What Alymsys is and what it is 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

1. What Alymsys is and what it is used for

The active substance in Alymsys is bevacizumab, a humanised monoclonal antibody (a type of protein normally produced by the immune system to help the body defend itself against infections and cancer). Bevacizumab binds selectively to a protein called vascular endothelial growth factor (VEGF), which is located in the walls of blood and lymphatic vessels in the body. The VEGF protein causes blood vessels to grow into the tumour, supplying it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumour growth by blocking the formation of new blood vessels that provide the nutrients and oxygen the tumour needs.

Alymsys is a medicine used to treat adult patients with advanced colorectal cancer. Alymsys will be given in combination with a chemotherapy regimen containing 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 administered together 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 administered in combination 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 renal cell carcinoma. When used in patients with kidney cancer, it will be administered together 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 administered in combination with carboplatin and paclitaxel.

In adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, Alymsys will be administered in combination with carboplatin and gemcitabine or with carboplatin and paclitaxel.

In adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a recurrence of their disease at least 6 months after 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 to treat adult 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 (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic (hypersensitive) to products derived from Chinese hamster ovary (CHO) cells or to other recombinant 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 perforations in the intestinal wall. If you have any condition causing inflammation in the abdomen (e.g., diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.

• Alymsys may increase the risk of developing abnormal connections between two organs or cavities. The risk of developing fistulas between the vagina and any part of the intestine may be increased if you have persistent, recurrent, or metastatic cervical cancer.

• Alymsys may increase the risk of bleeding or problems with surgical wound healing. If you are scheduled for surgery, have undergone major surgery within the last 28 days, or have an open surgical wound, you must not use this medicine.

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

• Alymsys may increase the risk of hypertension. If you have uncontrolled high blood pressure despite medication, consult 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 bulge and weakening in 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 thrombi in your arteries (a type of blood vessel) may increase if you are over 65 years old, have diabetes, or have previously had blood clots or thrombi in your arteries. Talk to your doctor, as blood clots or thrombi may lead to heart attack or stroke.

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

• Alymsys may cause bleeding, especially tumor-related bleeding. Consult your doctor if you have a personal or family history of bleeding disorders (coagulation disorders) or if you are taking blood-thinning medications for any reason.

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

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

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

• Alymsys may cause infections and reduce the number of neutrophils (a type of blood cell important for protection 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 experience headache, vision changes, confusion, or seizures (convulsions), with or without high blood pressure, consult your doctor.

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

Please consult your doctor even if any of the situations listed above apply to 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 heaviness in the jaw, or tooth loss, inform your doctor and dentist immediately.
• if you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Alymsys, especially if you are also receiving or have received an intravenous bisphosphonate injection.

Before starting treatment with Alymsys, you may be advised to have a dental examination.

Alymsys has been developed and manufactured for the treatment of cancer by intravenous injection. It has not been developed or manufactured for injection into the eye. Therefore, it is not authorized for this use. 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, small particles or spots in vision (floaters), eye pain,

• Seeing flashes of light with floaters, progressing to partial vision loss,

• Increased intraocular pressure,

• Bleeding in the eye.

Children and adolescents

The use of Alymsys is not recommended in children and adolescents under 18 years of age, as safety and benefit have not been established in these patients.

Other medicines and Alymsys

Tell your doctor, pharmacist, or nurse if you are taking, have recently taken, or might need to take any other medicines.

Combining Alymsys with another medicine called sunitinib malate (used for kidney and gastrointestinal cancer) may cause serious adverse effects. Consult your doctor to ensure you do not combine these medicines.

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

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

Pregnancy, breast-feeding, and fertility

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

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

You must not breast-feed during treatment with Alymsys and for at least 6 months after the last dose of Alymsys, as this medicine may interfere with your baby's growth and development.

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

Premenopausal women (women who have menstrual cycles) may notice their periods become irregular or stop and may experience fertility problems. 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 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 affecting your vision or concentration, or your reaction ability, do not drive or use machines until symptoms resolve.

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

Dosage and frequency of administration

The required dose of Alymsys depends on your body 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 appropriate dose of Alymsys for your case, and you will receive treatment 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 treatment until Alymsys is no longer able to inhibit tumor growth. Your doctor will discuss these aspects with you.

Method and route of administration

Do not shake the vial.

Alymsys is a concentrate for solution for infusion. Depending on the dose prescribed to you, a portion 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 to you as an intravenous infusion (a drip into your veins). The first infusion will be given over 90 minutes. If you tolerate this infusion well, the second infusion may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Administration of Alymsys must be temporarily interrupted:

• if you develop severe hypertension requiring treatment with antihypertensive medications,
• if you experience impaired wound healing after surgery,
• if you have recently undergone surgery.

Administration of Alymsys must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with antihypertensive medications; or if there is a sudden and severe increase in blood pressure,
• protein in the urine accompanied by body swelling,
• a perforation in the wall of the intestine,
• an abnormal tubular or fistulous connection between the trachea and esophagus (the tube leading to the stomach), 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), as deemed serious by your doctor,
• severe skin infections or deep skin layer infections,
• arterial embolism (blood clot) in the arteries,
• embolism in the pulmonary blood vessels,
• any severe bleeding.

If you use more Alymsys than you should

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

If you forget to use Alymsys

• your doctor will decide when your next dose of Alymsys should be administered. You must inform your doctor about this missed dose.

If you interrupt treatment with Alymsys

Interrupting treatment with Alymsys may reduce its effect on tumor growth. Do not interrupt 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 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 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. Signs may include: difficulty breathing or chest pain. You may also experience redness or flushing of the skin or rash, chills and shivering, feeling dizzy (nausea), or feeling unwell (vomiting).

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

Serious side effects that may be very common (may affect more than 1 in 10 patients) include:

• high blood pressure,
• sensation of numbness or tingling in hands or feet,
• decrease in blood cell counts, 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,
• tiredness,
• diarrhoea, nausea, vomiting, and abdominal pain.

Serious side effects that may be common (may affect up to 1 in 10 patients) include:

• perforation of the intestine,
• bleeding, including pulmonary haemorrhage in patients with non-small cell lung cancer,
• arterial blockage due to embolism,
• venous blockage due to embolism,
• blockage of blood vessels in the lungs due to embolism,
• blockage of leg veins due to embolism,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, sensitivity, pain, or blisters on fingers or feet,
• decrease in red blood cells,
• lack of energy,
• stomach and intestinal disturbances,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced or dark-coloured urine,
• inflammation of the mucosal lining of the mouth and intestine, lungs and airways, reproductive system, and urinary tract,
• sores in the mouth and in the tube connecting the mouth to the stomach, which may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal region pain,
• localized sites of pus,
• infection, and particularly blood or bladder infection,
• reduced 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 reduced oxygen levels in the blood,
• skin infections or infections of deeper layers beneath the skin,
• fistula: an abnormal tubular connection between internal organs and the skin or other tissues that are not normally connected, including connections between the vagina and intestine in patients with cervical cancer.

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

• severe skin infections or infections of deeper layers beneath the skin, especially if you had intestinal wall perforations or problems with wound healing,
• allergic reactions (signs may include difficulty breathing, facial redness, skin 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 further recommendations),
• brain disease with symptoms such as seizures (fits), headache, confusion, and vision disturbances (posterior reversible encephalopathy syndrome or PRES),
• symptoms suggesting changes in normal brain function (headaches, vision disturbances, confusion or seizures), and high blood pressure,
• enlargement and weakening of the wall of a blood vessel or tear in the blood vessel wall (aneurysms and arterial dissections),
• blockage of small blood vessels in the kidney,
• abnormally high pressure in the blood vessels of the lungs causing the right side of the heart to work harder than normal,
• perforation in the cartilage wall separating 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, bloating sensation, black stools, bloody stools, or blood in vomit),
• bleeding from the lower part of the large intestine,
• gum lesions with exposed jawbone that do not heal and may be associated with pain and inflammation of surrounding tissues (for further recommendations, see the list of side effects in the paragraph below),
• gallbladder perforation (symptoms and signs may include abdominal pain, fever, nausea, and vomiting).

If you notice any of these side effects listed above, seek medical attention as soon as possible.

Non-serious side effects that are very common (may affect more than 1 in 10 patients) are:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech disturbances,
• taste disturbances,
• runny nose,
• dry skin, skin peeling and inflammation, changes in skin colour,
• weight loss,
• nosebleeds.

Non-serious side effects that are common (may affect up to 1 in 10 patients) are:

• changes in voice and hoarseness.

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

• arterial embolism which may lead to stroke or heart attack,
• reduction in white blood cells and platelets (which help with clotting) in blood,
• diarrhoea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

Alymsys may also cause changes in laboratory tests performed by your doctor. These changes may include a reduction in white blood cell counts, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in the urine, decreased potassium, sodium, or phosphorus in blood, increased blood sugar, increased alkaline phosphatase (an enzyme) in blood, decreased haemoglobin (found in red blood cells and carries oxygen), which may be severe.

Reporting of side effects

If you experience any type of side effect, talk to your doctor, pharmacist, or nurse, even if these side effects are not listed in this leaflet. You can also report them directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide 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 expiry date stated on the carton and on the label of the vial after EXP. The expiry date refers to 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 infusion solution should be administered immediately after dilution. If not administered immediately, the storage times and conditions during use are the responsibility of the user and normally should not exceed 24 hours between 2°C and 8°C, unless the infusion solutions have been prepared under sterile conditions. When dilution takes place under sterile conditions, Alymsys will be stable after dilution for up to 30 days when stored between 2°C and 8°C, and for up to 48 hours at temperatures not exceeding 30°C.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the pack and other 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 components are trehalose dihydrate, monobasic sodium phosphate monohydrate, dibasic sodium phosphate, polysorbate 20, and water for injections (see section 2 “Alymsys contains sodium”).

Appearance of the product and contents of the pack

Alymsys is a concentrate for infusion solution (sterile concentrate). The concentrate is a colourless to brown or pale yellow liquid with opalescence, contained in a glass vial 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 Authorisation Holder

Mabxience Research SL
C/ Manuel Pombo Angulo 28 - 3rd and 4th floors
28050 Madrid
Spain

Manufacturer

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

Further information on this medicinal product is available from the local representative of the Marketing Authorisation Holder:

Iceland

Alvogen ehf.

Tel: +354 522 2900

Slovakia

Zentiva, a.s.

Tel: +421 2 3918 3010

Italy

Zentiva Italia S.r.l.

Tel: +39 02 38598801

Finland

Medical Valley Invest AB

Tel: +46 40 122131

Cyprus

Win Medica S.A.

Tel: +30 210 7488 821

Sweden

Medical Valley Invest AB

Tel: +46 40 122131

Latvia

Zentiva, k.s.

Tel: +371 67893939

Date of the most recent review of this leaflet:

Other sources of information

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