Mvasi 25 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

MVASI 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 questions, ask your doctor, pharmacist or nurse.
• If you experience any side effects, talk to your doctor, pharmacist or nurse, including any side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What MVASI is and what it is used for

The active substance in MVASI is bevacizumab, a humanized 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 tumor, supplying it with nutrients and oxygen. When bevacizumab binds to VEGF, it prevents tumor growth by blocking the formation of new blood vessels that provide the nutrients and oxygen the tumor needs.

MVASI is a medicine used to treat adult patients with advanced colorectal cancer. MVASI will be given in combination with a chemotherapy regimen containing a fluoropyrimidine medicine.

MVASI is also used to treat adult patients with metastatic breast cancer. When used in patients with breast cancer, MVASI will be administered together with a chemotherapeutic agent called paclitaxel or capecitabine.

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

MVASI 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). MVASI will be given in combination with erlotinib.

MVASI is also used to treat adult patients with advanced renal cell carcinoma. When used in patients with kidney cancer, MVASI will be administered together with another type of medicine called interferon.

MVASI 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, MVASI 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 a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, MVASI 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 a recurrence of their disease at least 6 months after their last treatment with a platinum-based chemotherapy regimen, MVASI will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

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

2. What you need to know before using MVASI

Do not use MVASI

• 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 cells (CHO) or to other recombinant human or humanized antibodies.
• if you are pregnant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with MVASI:

• MVASI may increase the risk of developing intestinal wall perforations. If you have any condition causing inflammation in the abdomen (e.g., diverticulitis, stomach ulcer, chemotherapy-induced colitis), consult your doctor.
• MVASI may increase the risk of developing abnormal connections (fistulas) 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.
• MVASI may increase the risk of bleeding or impaired wound healing. You must not use this medicine if you are scheduled for surgery, have undergone major surgery within the last 28 days, or have an unhealed surgical wound.
• MVASI may increase the risk of serious skin infections or deep skin layer infections, especially if you have had intestinal perforations or wound healing problems.
• MVASI 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 under control before starting treatment with MVASI.
• MVASI increases the risk of 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 had arterial clots or thrombi in the past. Consult your doctor, as clots or thrombi can lead to heart attack or stroke.
• MVASI may also increase the risk of developing blood clots or thrombi in veins (a type of blood vessel).
• MVASI may cause bleeding, particularly 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.
• MVASI may cause bleeding in and around your brain. Consult your doctor if you have metastatic cancer affecting your brain.
• MVASI may increase the risk of bleeding in your lungs, including coughing up blood or bloody sputum. Consult your doctor if you have previously experienced this.
• MVASI may increase the risk of heart weakening. 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 chest radiation therapy, or have a heart condition.
• MVASI may cause infections and reduce the number of neutrophils (a type of blood cell important for protection against bacteria).
• MVASI may cause hypersensitivity (including anaphylactic reactions) 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 MVASI treatment. If you experience headache, vision changes, confusion, or seizures (convulsions), with or without high blood pressure, consult your doctor.
• 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.

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

Before starting treatment with MVASI or during treatment with MVASI:

• if you have or have had mouth, teeth, and/or jaw pain, 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 MVASI (bevacizumab), especially if you are also receiving or have received intravenous bisphosphonate injections.

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

Children and adolescents

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

Cases of bone tissue death (osteonecrosis) in bones other than the jaw have been reported in patients under 18 years of age treated with bevacizumab.

Other medicines and MVASI

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

Combining MVASI with another medicine called sunitinib maleate (used for renal and gastrointestinal cancer) may cause serious adverse effects. Consult your doctor to ensure you are not taking these medicines together.

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

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

Pregnancy, breastfeeding, and fertility

You must not use MVASI if you are pregnant. MVASI 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 MVASI and for at least 6 months after the last dose of MVASI.

Inform your doctor immediately if you are already pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future.

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

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

Talk to your doctor, pharmacist, or nurse before using any medicine.

Driving and using machines

MVASI has not been shown to impair your ability to drive or operate tools or machines. However, drowsiness and fainting have been reported with the use of MVASI. If you experience symptoms affecting your vision or concentration, or your reaction ability, do not drive or use machines until symptoms resolve.

MVASI contains sodium

MVASI 25 mg/ml concentrate for solution for infusion (4 ml)

This medicine contains 5.4 mg of sodium (main component of table/cooking salt) per 4 ml vial. This corresponds to 0.3% of the maximum daily sodium intake recommended for an adult.

MVASI 25 mg/ml concentrate for solution for infusion (16 ml)

This medicine contains 21.7 mg of sodium (main component of table/cooking salt) per 16 ml vial. This corresponds to 1.1% of the maximum daily sodium intake recommended for an adult.

MVASI contains sodium and polysorbate 20

This medicine contains 1.6 mg of polysorbate 20 in each 100 mg/4 ml vial and 6.4 mg in each 400 mg/16 ml vial, equivalent to 0.4 mg/ml. Polysorbates may cause allergic reactions.

Consult your doctor if you have known allergies.

3. How to use MVASI

Dosage and frequency of administration

The required dose of MVASI 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 MVASI for your condition, and you will receive MVASI every 2 or 3 weeks. The number of infusions you receive will depend on your response to treatment, and treatment should continue until MVASI 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. MVASI is a concentrate for solution for infusion. Depending on the prescribed dose, either a portion or the entire content of the MVASI vial will be diluted with sodium chloride solution prior to administration. A doctor or nurse will administer this diluted MVASI 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 may be administered over 60 minutes. Subsequent infusions may be administered over 30 minutes.

Administration of MVASI must be temporarily interrupted if you:

• develop severe hypertension requiring treatment with blood pressure medications,
• experience impaired wound healing after surgery,
• have recently undergone surgery.

Administration of MVASI must be permanently discontinued if you have:

• severe hypertension that cannot be controlled with blood pressure 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 intestinal wall;
• a serious abnormal tubular or fistulous connection between the trachea and the 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 normally not connected (fistula), as determined by your doctor;
• severe skin infections or deep skin layers infections;
• arterial embolism (blood clot in the arteries);
• embolism in the pulmonary blood vessels;
• any severe bleeding.

If you use more MVASI 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 MVASI

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

If you stop treatment with MVASI

Stopping treatment with MVASI may reduce its effect on tumor growth. Do not discontinue treatment with MVASI 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 everyone will experience them.

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects not listed in this leaflet.

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

Allergic reactions

If you experience 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), swelling, dizziness, rapid heartbeat, and loss of consciousness.

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

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

• high blood pressure,
• numbness or tingling sensation 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,
• fatigue,
• diarrhea, nausea, vomiting, and abdominal pain.

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

• intestinal perforation,
• bleeding, including pulmonary hemorrhage 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 pulmonary embolism,
• blockage of leg veins due to embolism,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, sensitivity, pain, or blistering on fingers or feet,
• decrease in red blood cell count,
• lack of energy,
• gastrointestinal disturbances,
• muscle and joint pain, muscle weakness,
• dry mouth combined with thirst and/or reduced or dark-colored urine,
• inflammation of the mucosal lining of the mouth and intestine, lungs and airways, reproductive organs, and urinary tract,
• mouth sores and sores in the tube connecting the mouth to the stomach (esophagus), which may be painful and cause difficulty swallowing,
• pain, including headache, back pain, pelvic pain, and anal region pain,
• localized areas of pus,
• infection, particularly blood or bladder infection,
• reduced blood supply to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulse),
• intestinal obstruction,
• abnormal urine test (proteins in urine),
• difficulty breathing or reduced oxygen levels in the blood,
• skin infections or infections in 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,
• allergic reactions (signs may include difficulty breathing, facial redness, skin rash, low or high blood pressure, low oxygen levels in blood, chest pain, or nausea/vomiting).

Serious adverse effects that may be rare (may affect up to 1 in 1,000 patients) include:

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

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

• severe skin infections or infections in deeper layers beneath the skin, especially if you had intestinal wall perforations or problems with wound healing,
• 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,
• blockage of small blood vessels in the kidneys,
• abnormally high pressure in 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 of 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 adverse effects in the paragraph below),
• gallbladder perforation (symptoms and signs may include abdominal pain, fever, nausea, and vomiting),
• enlargement and weakening of a blood vessel wall or tearing of a blood vessel wall (aneurysms and arterial dissections).

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

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

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• speech disturbances,
• altered taste,
• nasal discharge,
• dry, peeling, and inflamed skin, changes in skin color,
• weight loss,
• nosebleeds.

Non-serious adverse effects that are common (may affect up to 1 in 10 people) 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,
• diarrhea,
• malaise,
• headache,
• fatigue,
• high blood pressure.

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

Pain in the mouth, teeth, and/or jaw, swelling or sores in the mouth, numbness or heaviness in the jaw, or tooth loss. These may be signs and symptoms of jaw bone damage (osteonecrosis). Inform your doctor and dentist immediately if you experience any of these.

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.

MVASI has been developed and manufactured for the treatment of 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 bevacizumab 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 vision (floaters), eye pain,
• flashes of light with floaters progressing to partial vision loss,
• increased eye pressure,
• bleeding in the eye.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects not listed in this leaflet.

You can also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of MVASI

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 following EXP. The expiry date refers to the last day of the stated month.

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 diluted solution for infusion should be administered immediately after dilution. If not administered immediately, the storage times and conditions during use are the responsibility of the user and would normally not exceed 24 hours at between 2°C and 8°C, unless the infusion solutions have been prepared under sterile conditions. When dilution has been performed under sterile conditions, MVASI remains stable for 35 days at between 2°C and 8°C plus an additional 48 hours at temperatures not exceeding 30°C.

Do not use MVASI 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. Package contents and other information

Composition of MVASI

• The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab.
• Each 4 ml vial of concentrate contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.
• Each 16 ml vial of concentrate contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.
• The other components are trehalose dihydrate, sodium phosphate, polysorbate 20 (E 432) (see section 2 “MVASI contains sodium and polysorbate 20”), and water for injections.

Presentation of the product and contents of the container

MVASI is a concentrate for solution for infusion. The concentrate is a clear to slightly opalescent, colourless to slightly yellow liquid 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 MVASI pack contains one vial.

Marketing Authorisation Holder and Manufacturer

Amgen Technology (Ireland) UC,

Pottery Road,

Dun Laoghaire,

Co. Dublin,

Ireland

Marketing Authorisation Holder

Amgen Technology (Ireland) UC,

Pottery Road,

Dun Laoghaire,

Co. Dublin,

Ireland

Manufacturer

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

Manufacturer

Amgen NV

Telecomlaan 5-7

1831 Diegem

Belgium

For more information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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 (EMA) http://www.ema.europa.eu.