Leaflet: information for the user

Fludarabine Accord 25 mg/ml concentrate for injection and for infusion

Fludarabine phosphate

Read this 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.
• This medicine has been prescribed for you only and should not be given to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

6.Contents of the pack and additional information

Fludarabina Accord contains the active substance fludarabina that stops the growth of new cancer cells. All cells in the body produce new cells similar to themselves through division. Fludarabina Accord is incorporated by cancer cells and paralyzes their division.

In leukemias of white blood cells (such aschronic lymphocytic leukemia), the body produces many abnormal white blood cells, and lymph nodes begin to grow in various parts of the body. The abnormal growth of white blood cells prevents the normal functions of fighting disease, and can displace healthy blood cells. This can result in infections, decrease in the number of red blood cells (anemia), bruises, abnormal severe bleeding, or even organ failure.

Fludarabina Accord is used for the treatment of chronic lymphocytic leukemia of B cells (CLL-B) in patients with sufficient production of healthy blood cells.

The first treatment in chronic lymphocytic leukemia with Fludarabina Accord should only be initiated in patients with advanced disease who present symptoms related to the disease or evidence of disease progression.

No use Fludarabina Accord:

• If you are allergicto fludarabine phosphate or any of the other components of this medication (listed in section 6).
• If you are breastfeeding
• If you have severe kidney problems.
• If you have a low red blood cell countdue to a certain type of anemia (severe hemolytic anemia). Your doctor will have told you if you have this problem.

If you think any of these may apply to you, inform your doctor.

Warnings and precautions

Inform your doctor before using Fludarabina Accord

• If yourbone marrowdoes not function properly or if yourimmune systemdoes not function well or is depressed or has a history ofserious infections.

Your doctor may decide not to give you this medicine, or may take preventive measures.

• If you feel very unwell, observe unusual bruising, more bleeding than usual after a wound, or if you think you are getting many infections.

• If during treatment your urine is red or brown, or if you have a rash or blister on your skin.

These symptoms may be signs of a decrease in blood cells, which can be caused by the disease itself or by treatment. This can last up to a year, regardless of whether you have received treatment with this medicine before or not. During treatment with Fludarabina Accord, your immune system may also attack different parts of your body, or your red blood cells (called "autoimmune disorders"). These problems can be potentially fatal. If this happens, your doctor will stop treatment and you may receive other medicines such as irradiated blood transfusions (see below) and corticosteroids.

You will have regular blood tests during treatment and will be closely monitored while being treated with this medicine.

• If you notice any unusual symptoms in your nervous system, such as vision changes, headache, confusion, convulsions.

If Fludarabina Accord is used for a long time, its effects on the central nervous system are unknown. However, patients treated with the recommended dose for up to 26 treatment cycles were able to tolerate it.

When Fludarabina Accord is used at the recommended dose, after treatment with other medicines or at the same time as some other medicines, the following adverse effects have been reported: neurological disorders manifested by headache, dizziness, nausea, vomiting, convulsions, visual disturbances including loss of vision, changes in mental state (abnormal thinking, confusion, altered consciousness) and occasionally neuromuscular disorders manifested by muscle weakness in the limbs (including partial or complete irreversible paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS).

In patients receiving four times the recommended dose, blindness, coma, and death have been reported. Some of these symptoms appeared with a delay of around 60 days or more after treatment was stopped.In some patients treated with Fludarabina Accord at doses higher than recommended, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL), or reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported. The same symptoms of LE, ATL, or RPLS, described above, may occur.

LE, ATL, and RPLS may be irreversible, potentially fatal, or fatal.

Fludarabina Accord treatment should be stopped for further investigation whenever LE, ATL, or RPLS is suspected.

If LE, ATL, or RPLS is confirmed, your doctor will stop your treatment with Fludarabina Accord.

• If you notice any pain in the side, blood in the urine, or decreased urine output,

When your disease is very severe, your body may not be able to eliminate all the waste productsfrom the cells destroyed by Fludarabina Accord. This is calledtumor lysis syndromeand cancause kidney failure and heart problemsfrom the first week of treatment. Your doctor is aware of this and may give you other medicines to prevent it.

• If you need to have stem cells extracted and are being treated with Fludarabina Accord (or have been),

• If you need a blood transfusion and are being treated with Fludarabina Accord (or have been),

If you need a blood transfusion, your doctor will ensure that you only receive irradiated blood. Severe complications, including death, have been reported from non-irradiated blood transfusions.

• If you notice any change in your skin while receiving this medicine or after treatment has ended,

• If you have skin cancer (or have had it)it may worsen or recur during treatment with Fludarabina Accord or later. You may develop skin cancer during or after treatment with Fludarabina Accord.

Other aspects to consider while being treated with Fludarabina Accord:

• Men and women of childbearing age should adopt effective contraceptive measuresduring treatment and for at least 6 months afterwards. It cannot be ruled out that Fludarabina Accord may harm an unborn baby. Your doctor will carefully weigh the benefits of your treatment against the potential risk to the unborn baby and, if you are pregnant, will only prescribe Fludarabina Accord if it is strictly necessary.

• If you intend to breastfeedor are breastfeeding, do not start or continue while being treated with Fludarabina Accord.

• If you need a vaccination, consult your doctor,as live vaccines should be avoided during treatment with Fludarabina Accord and after.

• If you have kidney problems or are over 65 years old,you will have regular blood tests and/or laboratory tests to monitor your kidney function(see also sections 2 and 3).

Children and adolescents:

The safety and efficacy of Fludarabina Accord in children under 18 years have not been established. Therefore, the use of this medicine is not recommended in children.

Patients over 65 years old and Fludarabina Accord:

If you are over 65 years old, you will have regular kidney function tests (see also section 3. How to use Fludarabina Accord). If you are over 75 years old, you will be closely monitored.

Other medicines and Fludarabina Accord:

Inform your doctor if you are using, have used recently, or may need to use any other medicine, including any medicine obtained without a prescription.

It is especially important to inform your doctor about:

• pentostatin(deoxycoformycin), also used to treat CLL-B. Taking these two medicines together can lead to severe pulmonary complications.
• dipyridamole, used to prevent excessive blood clotting or other similar medicines. They may reduce the effectiveness of Fludarabina Accord.
• cytarabine(Ara-C) used to treat chronic lymphocytic leukemia. If Fludarabina Accord is combined with cytarabine, they may increase the levels of the active form of Fludarabina Accord in leukemic cells. However, it has not been shown that they have changed global blood levels and their elimination from the blood.

Pregnancy, breastfeeding, and fertility:

Pregnancy

Fludarabina Accord should not be administered to women who are pregnant, as animal studies and limited human experience have shown the existence of a possible risk of abnormalities in the unborn baby, as well as early pregnancy loss and premature birth.

• If you are pregnant, think you may be pregnant, or are planning to become pregnant, inform your doctor immediately.

Your doctor will carefully weigh the benefits of your treatment against the potential risk to the unborn baby and, if you are pregnant, will only prescribe Fludarabina Accord if it is strictly necessary.

Lactation:

You should not start or continue breastfeeding during treatment with this medicine, as it may interfere with the growth and development of your baby..

Fertility:

Men and women who are fertile should use effective contraceptive measures during treatment and for at least 6 months afterwards.

Driving and operating machinery

Some people may feel tired, weak, have visual disturbances, be confused, agitated, or have convulsions while receiving treatment with Fludarabina Accord. Do not drive or operate machinery until you are sure it does not affect you.

Fludarabina Accord contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per dose, so it is considered essentially "sodium-free".

Follow exactly the administration instructions of this medication indicated by your doctor. In case of doubt, consult your doctor again.

Fludarabina Accord must be administered under the supervision of a qualified doctor with experience in the use of cancer therapy.

• For information on the preparation of the diluted solution, see section 6. Contents of the package and additional information.

How much Fludarabina Accord is administered:

The prescribed dose will depend on your body surface area. This is measured in square meters (m2), and is determined by your doctor from your height and weight.

The recommended dose is 25 mg of fludarabine phosphate/m2of body surface area.

How Fludarabina Accord is administered:

Fludarabina Accord is administered in the form of a solution as an injection or, in most cases, as an infusion.

An infusion means that the medication is administered directly into the circulatory system through a drip into a vein.

An infusion lasts approximately 30 minutes.

Your doctor will ensure that Fludarabina Accord is not administered outside the vein (paravenously). However, if this happens, no severe local adverse reactions have been reported.

For how long Fludarabina Accord is administered:

The dose will be administeredonce a day for 5 consecutive days.

This 5-day treatment cycle will be repeated every 28 daysuntil your doctor decides that the best effect has been achieved (usually after 6 cycles).

The duration of treatment depends on the results obtained and the tolerance to Fludarabina Accord. The next cycle may be delayed if adverse effects are a problem.

You will have regular blood tests during your treatment. Your individual dose will be carefully adjustedaccording to the number of your blood cells and your response to treatment.

Your dose may be reduced if adverse effects are a problem.

If you have kidney problems or are over 65 years old, you will have regular tests to check your kidney function. If your kidneys do not function properly, you may be given a lower dose of this medication. If your kidney function is severely reduced, you will not be given this medication at all(see also section 2).

If some of the Fludarabina Accord solution spills accidentally:

If some of the Fludarabina Accord solution comes into contact with your skin or the mucous membranes of your nose or mouth, wash the area thoroughly with water and soap. If the solution gets into your eyes, rinse them thoroughly with plenty of tap water. Avoid any inhalation exposure.

If you receive more Fludarabina Accord than you should:

If you receive an overdose, your doctor will stop treatment and treat the symptoms. High doses may also lead to a severely reduced number of blood cells.

For fludarabine administered intravenously, it has been reported that an overdose can cause late blindness, coma, and even death.

If you forget a dose of Fludarabina Accord:

Your doctor will establish the times when you will receive this medication. If you think you may have forgotten a dose, talk to your doctor as soon as possible.

If you interrupt treatment with Fludarabina Accord before it is finished:

You and your doctor may decide to stop your treatment with Fludarabina Accord solution if the adverse effects are becoming too severe.

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them. If you are not sure what the adverse reactions described below are, ask your doctor to explain them to you.

Some serious side effects can be potentially fatal.

• If you have difficulty breathing, have a cough, or have chest pain with or without fever.These may be signs of a lung infection.
• If you notice unusual bruising, more bleeding than usual after an injury, or if you think you are getting many infections.These may be caused by a decrease in the number of blood cells. This can also lead to an increased risk of serious infections (opportunistic infections) caused by organisms that normally do not cause diseases in healthy people(opportunistic infections)including a late reactivation of viruses, for example, herpes zoster.
• If you notice any chest pain, blood in the urine, or decreased urine output.These may be signs oftumour lysis syndrome(see section 2).
• If you notice a skin and/or mucous membrane reaction with redness, inflammation, blisters, and tissue rupture.These may be signs of a severe allergic reaction (Stevens-Johnson syndrome, Lyell syndrome).
• If you have palpitations (if you suddenly become aware of your heartbeat) or chest pain.These may be signs of heart problems.

Inform your doctor immediately if you notice any of these side effects.

The following are possible side effects listed by how often they occur.Rare side effects (less than 1 in 1,000 patients) were identified primarily from post-marketing experience.

Very common(may affect more than 1 in 10 people):

• Infections (some serious);
• Infections due to a suppressed immune system (opportunistic infections);
• Lung infection(pneumonia)with possible symptoms such as difficulty breathing and/or cough with or without fever;
• Decrease in the number of blood cells in the blood(thrombocytopenia)with possibility of bruising and bleeding;
• Decrease in the number of white blood cells(neutropenia);
• Decrease in the number of red blood cells(anemia);
• Cough;
• Vomiting, diarrhea, general feeling of discomfort(nausea);
• Fever;
• Feeling tired(fatigue);
• Weakness.

Common(may affect up to 1 in 10 people)

• Other types of blood cancer(myelodysplastic syndrome, acute myeloid leukemia).The majority of patients with these diseases were previously treated or treated at the same time or later with other cancer medications(alkylating agents, topoisomerase inhibitors)or radiation therapy.
• Medullary depression(myelosuppression);
• Severe loss of appetite leading to weight loss (anorexia);
• Numbness or weakness in limbs (peripheral neuropathy);
• Altered vision;
• Inflammation of the inside of the mouth(stomatitis);
• Skin eruptions;
• Swelling due to excessive fluid retention (edema);
• Inflammation of the mucous membranes of the digestive system from the mouth to the anus (mucositis);
• Chills;
• General feeling of discomfort.

Uncommon(may affect up to 1 in 100 people).

• Autoimmune disorder (see 2"Warnings and precautions").
• Tumour lysis syndrome (see 2"Warnings and precautions");
• Confusion;
• Pulmonary toxicity; lung scarring(pulmonary fibrosis), lung inflammation(pneumonitis), difficulty breathing(dyspnea);
• Bleeding in the stomach or intestines;
• Abnormal levels of liver or pancreatic enzymes;

Rare(may affect up to 1 in 1,000 people).

• Lymphatic system disorders due to viral infection(lymphoproliferative disorder associated with VEB);
• Coma;
• Seizures
• Agitation;
• Blindness;
• Inflammation or damage to the optic nerve (optic neuritis; optic neuropathy);
• Heart failure;
• Cardiac arrhythmias.
• Skin cancer
• Reaction in the skin and/or mucous membrane with redness, inflammation, blisters, and tissue rupture. (Stevens-Johnson syndrome, Lyell syndrome).

• Unknown (cannot be calculated from available data)Inflammation of the bladder, which may be painful when urinating, and may lead to blood in the urine (hemorrhagic cystitis).
• Bleeding in the brain.
• Bleeding in the lungs
• The neurological disorders manifested by headache, dizziness(nausea) and vomiting, seizures, visual disturbances including loss of vision, changes in mental state (abnormal thinking, confusion, altered consciousness), and occasionally the neuromuscular disorders manifest by weakness in limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS)).

Reporting of adverse reactions

If you experience any type of adverse reaction, consult your doctor, even if it is a possible adverse reaction that does not appear in this leaflet. You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es. By reporting adverse reactions, you can contribute to providing more information on the safety of this medicine.

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

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

• Unopened vials

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

• After dilution

The physical and chemical stability in use has been demonstrated at 0.2 mg/ml and 6.0 mg/ml after dilution with sodium chloride 0.9% and 5% glucose solution for 7 days at 2-8°C and 5 days at 20-25°C in non-PVC bags and glass bottles.

From a microbiological point of view, the product should be used immediately. If not used immediately, the storage times and conditions in use before administration are the responsibility of the user and should not exceed 24 hours at 2-8°C unless the dilution took place in validated and controlled aseptic conditions.

For information for healthcare professionals and medical doctors, see section 6. Contents of the pack and additional information.

Do not use this medication if you observe any visible sign of deterioration.

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

Composition of Fludarabine Accord:

• The active ingredient isfludarabine phosphate. Each ml contains 25 mg of fludarabine phosphate
• The other components (excipients) aremannitol, disodium hydrogen phosphate dihydrate, and water for injection preparations.

Fludarabine Accord is supplied in glass vials of 2 ml.

Appearance of Fludarabine Accord and contents of the pack:

Fludarabine Accord is a transparent, colourless or slightly yellow-brown solution contained in a transparent glass vial.

Fludarabine Accord is available in three pack sizes containing 1 vial, 5 vials or 10 vials.

Only some pack sizes may be marketed.

Marketing Authorisation Holder:

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Manufacturer:

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice

Poland

or

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

This medicinal product has been authorised in the following EEA countries with the following names:

Last review date of this leaflet: May 2023

For detailed and updated information on this medicinal product, please consult the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es

The following information is intended only for healthcare professionals

Fludarabine Accord, like other cytotoxic medicinal products, should be prepared by qualified personnel in a designated area. Manipulation and disposal procedures should be carried out in accordance with the guidelines used for cytotoxic medicinal products.

For intravenous use only.

Incompatibilities

Given the absence of compatibility studies, this medicinal product should not be mixed with other products.

Dilution

The required dose (calculated on the basis of the patient's body surface area) is drawn up into a syringe.

To administer the dose intravenously in a bolus, this dose is diluted further with 10 ml of sodium chloride 9 mg/ml (0.9%). Alternatively, to administer the dose by infusion, the required dose may be diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) and infused over approximately 30 minutes.

In clinical studies, the product has been diluted in 100 ml or 125 ml of 5% dextrose solution for injection or sodium chloride 9 mg/ml (0.9%).

Storage

Packaged for marketing: 2 years.

The physical and chemical stability in use has been demonstrated at 0.2 mg/ml and 6.0 mg/ml after dilution with sodium chloride 0.9% and glucose 5% solution for 7 days at 2-8°C and 5 days at 20-25°C in non-PVC bags and glass bottles.

From a microbiological point of view, the product should be used immediately. If not used immediately, the storage times and conditions in use before administration are the responsibility of the user and should not exceed 24 hours at 2-8°C unless the dilution has taken place in validated and controlled aseptic conditions.

Inspection before use

The diluted solution should be transparent, colourless or slightly yellow-brown. It should be visually inspected before use.

Only transparent, colourless or slightly yellow-brown solutions without particles should be used. Fludarabine Accord should not be used if the container is defective.

Handling and disposal

Fludarabine Accord should not be handled by pregnant women.

Procedures should be followed for the proper handling, which will be carried out in accordance with local requirements for cytotoxic medicinal products.

Care should be taken in the handling and preparation of the Fludarabine Accord solution. The use of latex gloves and safety glasses is recommended to avoid the risk of contact in the event of a vial break or accidental spillage. If the solution comes into contact with the skin or mucous membranes, the affected area should be thoroughly washed with water and soap. In the event of eye contact, the eyes should be flushed with plenty of water. Exposure by inhalation should also be avoided.

This medicinal product is for single use only. The disposal of unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations.