Package leaflet: Information for the user

Introduction

Package leaflet: Information for the patient

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

Contents of the leaflet

What Aybintio is and what it is used for
What you need to know before using Aybintio
How to use Aybintio
Possible side effects
How to store Aybintio
Contents of the pack and other information

1. What Aybintio is and what it is used for

The active substance of Aybintio 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 blood vessels that provide the nutrients and oxygen the tumor needs.

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

Aybintio 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.

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

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

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

Aybintio 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.

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, Aybintio 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, Aybintio will be administered in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin.

Aybintio is also used to treat adult patients with persistent, recurrent, or metastatic cervical cancer. Aybintio will be given 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 Aybintio

Do not use Aybintio

if you are allergic (hypersensitive) to bevacizumab or to any of the other components 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 starting to use Aybintio:

Aybintio 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.
Aybintio may increase the risk of developing an abnormal connection 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.
This medicine may increase the risk of bleeding or problems with surgical 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.
Aybintio may increase the risk of developing serious skin infections or deep skin layer infections, especially if you have had intestinal wall perforations or wound healing problems.
Aybintio 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 Aybintio.
If you have or have had an aneurysm (a bulge and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.
This medicine 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 previously had arterial clots or thrombi. Consult your doctor, as clots or thrombi can lead to heart attack and stroke.
Aybintio may also increase the risk of developing blood clots or thrombi in your veins (a type of blood vessel).
This medicine may cause bleeding, especially tumor-related bleeding. Consult your doctor if you have a tendency or family history of bleeding disorders (coagulation disorders) or if you are taking blood-thinning medications for any reason.
Aybintio may cause bleeding in and around your brain. Consult your doctor if you have metastatic cancer affecting your brain.
Aybintio 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.
Aybintio 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 radiotherapy, or have a heart condition.
This medicine may cause infections and reduce the number of neutrophils (a type of blood cell important for protection against bacteria).
Aybintio 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 Aybintio treatment. If you experience headache, vision changes, confusion, or seizures (with or without high blood pressure), consult your doctor.

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

Before starting treatment with Aybintio or during treatment with Aybintio:

if you have or have had mouth, tooth, 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 Aybintio, especially if you are also receiving or have received intravenous bisphosphonates.

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

Children and adolescents

Use of Aybintio 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 Aybintio.

Other medicines and Aybintio

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

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

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

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

Pregnancy, breastfeeding, and fertility

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

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

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

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

Consult your doctor, pharmacist, or nurse before using any medicine.

Driving and using machines

Aybintio 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 Aybintio. If you experience symptoms affecting your vision or concentration, or your reaction ability, do not drive or operate machinery until symptoms resolve.

Aybintio contains sodium and polysorbate 20

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

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 Aybintio

Dosage and frequency of administration

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

Administration of Aybintio must be temporarily interrupted if you:

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

Administration of Aybintio must be permanently discontinued if you have:

severe hypertension that cannot be controlled with antihypertensive medications, or 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 connection or fistula 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, as determined by your doctor,
severe infections of the skin or deep layers of the skin,
arterial embolism (blood clot in the arteries),
embolism in the pulmonary blood vessels,
any severe bleeding.

If you use more Aybintio 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 Aybintio

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

If you interrupt treatment with Aybintio

Interrupting treatment with Aybintio may reduce its effect on tumor growth.

Do not interrupt treatment with Aybintio unless you have consulted 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 type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet.

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

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 skin redness or flushing, rash, chills and shivering, dizziness (nausea), or feeling unwell (vomiting), swelling, dizziness, rapid heartbeat, or loss of consciousness.

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

Serious adverse effects that may be very common (may affect more than 1 in 10 patients) 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 between 1 and 10 out of 100 patients) 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,
pulmonary blood vessel blockage due to embolism,
leg vein blockage 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 cell count,
lack of energy,
stomach and intestinal 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,
sores in the mouth and 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 pus formation,
infection, particularly blood or bladder infection,
reduced blood flow 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 1000 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,
widening and weakening of the wall of a blood vessel or tear in the blood vessel wall (arterial aneurysms and 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 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).

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

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

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 color,
weight loss,
nosebleeds.

Non-serious adverse effects that are common (affect between 1 and 10 out of 100 patients) include:

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 cell and platelet counts (which aid in clotting) in the blood,
diarrhea,
malaise,
headache,
fatigue,
high blood pressure.

Aybintio may also cause changes in laboratory tests performed by your doctor. These changes may include a decrease in white blood cells, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of proteins in urine, decreased potassium, sodium, or phosphorus levels in blood, increased blood sugar, increased alkaline phosphatase (an enzyme) in blood, decreased hemoglobin (found in red blood cells and responsible for oxygen transport), which may 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 that 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.

Aybintio has been developed and manufactured for the treatment of cancer via 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 Aybintio is injected directly into the eye (off-label use), the following side 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.

Reporting of adverse effects

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

5. Storage of Aybintio

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 unopened vial may be stored at temperatures not exceeding 30°C for a maximum of 35 days. The vial must be discarded if not used within 35 days after removal from the refrigerator, even if it has been returned to the refrigerator during this period.

The diluted solution for infusion should be administered immediately. If not administered immediately, the storage times and conditions during use are the responsibility of the user and normally would not exceed 24 hours at 2°C to 8°C, unless the infusion solutions have been prepared under sterile conditions. When dilution has taken place under sterile conditions, Aybintio is stable for 45 days at 2°C to 8°C plus an additional 72 hours at temperatures not exceeding 30°C.

Do not use Aybintio 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 containers that you no longer need. This will help protect the environment.

6. Contents of the container and other information

Composition of Aybintio

The active substance is bevacizumab.

Each ml of concentrate contains 25 mg of bevacizumab.

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 acetate trihydrate, acetic acid, polysorbate 20 (E 432) (see section 2 “Aybintio contains sodium and polysorbate 20”), and water for injections.

Appearance of the product and contents of the container

Aybintio is a concentrate for solution for infusion. The concentrate is a colourless to pale brown, clear 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 Aybintio pack contains one vial.

Marketing Authorisation Holder

Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

The Netherlands