FLUDARABINE ACCORD 25 mg/mL Concentrate for Injection and Infusion Solution

Introduction

Package Leaflet: Information for the User

Fludarabina Accord 25 mg/ml concentrate for solution for injection and infusion

Fludarabine phosphate

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

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What is Fludarabina Accord and what is it used for
2. What you need to know before you use Fludarabina Accord
3. How to use Fludarabina Accord
4. Possible side effects
5. Storing Fludarabina Accord

1. Contents of the pack and other information

1. What is Fludarabina Accord and what is it used for

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

In white blood cell cancers (such as chronic 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 cells from the blood. This can result in infections, a decrease in the number of red blood cells (anemia), bruising, abnormal bleeding or even organ failure.

Fludarabina Accord is used to treat B-cell chronic lymphocytic leukemia (B-CLL) in patients with sufficient production of healthy blood cells.

Treatment with Fludarabina Accord alone should only be started in patients with advanced disease who have symptoms related to the disease or evidence of disease progression.

2. What you need to know before you use Fludarabina Accord

Do not use Fludarabina Accord:

• If you are allergicto fludarabine phosphate or to any of the other ingredients of this medicine (listed in section 6).
• If you are breast-feeding
• If you have severe kidney problems.
• If you have a low number of red blood cellsdue to a certain type of anemia (uncompensated hemolytic anemia). Your doctor will have told you if you have this problem.

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

Warnings and precautions

Tell your doctor before using Fludarabina Accord

• If your bone marrowis not working properly or if your immune systemis not working well or is depressed or you have a history of severe infections.

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

• If you feel very unwell, notice unusual bruising, more bleeding than usual after an injury, or if you think you have many infections.

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

These symptoms may be signs of a decrease in the number of blood cells, which can be caused by the disease itself or by the treatment. It can last up to a year, regardless of whether you have received treatment before with this medicine 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 the treatment and you may receive other medicines such as irradiated blood transfusion (see below) and adrenocorticoids.

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, seizures.

If Fludarabina Accord is used for a long period, its effects on the central nervous system are unknown. However, patients treated with the recommended dose for up to 26 cycles of treatment 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 side effects have been reported: neurological disorders manifested by headache, feeling of dizziness (nausea) and vomiting, seizures, visual disturbances including loss of vision, changes in mental status (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, toxic acute leukoencephalopathy or reversible posterior leukoencephalopathy syndrome (PRES).

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

LE, ATL, and PRES could be irreversible, potentially fatal or fatal.

If LE, ATL, or PRES are suspected, treatment with Fludarabina Accord should be stopped for further investigation.

If the diagnosis of LE, ATL, or PRES is confirmed, your doctor will stop your treatment with Fludarabina Accord.

• If you notice any pain in your side, blood in your urine or a decrease in the amount of urine,

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

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

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

If you need a blood transfusion, your doctor will make sure you only receive blood that has been treated with irradiation. From non-irradiated blood transfusions, serious complications and even death have occurred.

• If you notice any changes in your skin while receiving this medicine or after finishing treatment,

• 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 must use effective contraceptive measuresduring treatment and for at least 6 months after. 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 possible risk to the unborn baby and, if you are pregnant, Fludarabina Accord will only be given to you if it is strictly necessary.

• If you are breast-feedingor are in the lactation period, you should not start or continue while being treated with Fludarabina Accord.

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

• If you have kidney problems or if you are over 65 years old,you will regularly have blood tests and/or laboratory tests to monitor your kidney function (see also section 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.

Elderly patients and Fludarabina Accord:

If you are over 65 years old, you will regularly have tests to check your kidney function, (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:

Tell your doctor if you are using, have recently used or might use any other medicines, including any medicines obtained without a prescription.

It is especially important to tell your doctor about:

• pentostatin(deoxicoformycin), also used to treat B-CLL. Taking these two drugs together can lead to serious lung 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 lymphatic leukemia. If Fludarabina Accord is combined with cytarabine, it may increase the levels of the active form of Fludarabina Accord in leukemic cells. However, it has not been shown that global levels in blood and its elimination from the blood have changed.

Pregnancy, breast-feeding and fertility:

Pregnancy

Fludarabina Accord should not be given to women who are pregnant, because animal studies and limited human experience have shown 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, tell your doctor immediately.

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

Breast-feeding:

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

Fertility:

Men and women who are fertile must use effective contraceptive methods during treatment and for at least 6 months after.

Driving and using machines

Some people may feel tired, weak, have vision changes, be confused, agitated or have seizures while receiving treatment with Fludarabina Accord. Do not attempt to drive or operate machinery until you are sure that 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 essentially "sodium-free".

3. How to use Fludarabina Accord

Follow the instructions for administration of this medicine exactly as told by your doctor. If you are unsure, ask your doctor again.

Fludarabina Accord should 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 pack and other information.

How much Fludarabina Accord is given:

The prescribed dose will depend on your body surface area. This is measured in square meters (m2), and is determined by your doctor based on your height and weight. The recommended dose is 25 mg of fludarabine phosphate/m2 of body surface area.

How Fludarabina Accord is given:

Fludarabina Accord is given as a solution by injection or, in most cases, by infusion.

An infusion means that the medicine is given directly into the bloodstream through a drip into a vein.

An infusion lasts approximately 30 minutes.

Your doctor will make sure that Fludarabina Accord is not given outside the vein (paravenously). However, if this happens, no serious local adverse reactions have been reported.

For how long Fludarabina Accord is given:

The dose will be given once 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).

How long the treatment lasts depends on the results obtained and tolerance to Fludarabina Accord. The next cycle may be delayed if side 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.

The dose may be reduced if side effects are a problem.

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

If some of the Fludarabina Accord solution accidentally spills:

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 the treatment and treat the symptoms. High doses may also lead to a severely reduced number of blood cells.

For fludarabine given by intravenous route, it has been reported that overdose may cause late blindness, coma, and even death.

If you miss a dose of Fludarabina Accord:

Your doctor will decide when you will receive this medicine. If you think you may have missed a dose, talk to your doctor as soon as possible.

If you stop treatment with Fludarabina Accord prematurely:

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

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

4. Possible Adverse Effects

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

Some serious adverse effects can be potentially life-threatening.

• If you have difficulty breathing, have a cold, 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 seem to be 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 infections (severe) caused by organisms that do not normally cause disease in healthy people (opportunistic infections)including late reactivation of viruses, e.g. herpes zoster.
• If you notice any pain in the side, blood in the urine, or a decrease in the amount of urine. These may be signs of tumor lysis syndrome(see section 2).
• If you notice a skin and/or mucous membrane reaction with redness, inflammation, blisters, and tissue breakdown.These may be signs of a severe allergic reaction (Lyell's syndrome, Stevens-Johnson syndrome).
• If you have palpitations (if you suddenly notice your heartbeat) or chest pain. These may be signs of heart problems.

Tell your doctor immediately if you notice any of these effects.

The following are possible adverse effects according to their frequency. Rare adverse effects (less than 1 in 1,000 patients) were identified mainly from post-marketing experience.

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

• Infections (some severe);
• Infections due to a weakened immune system (opportunistic infections);
• Lung infection (pneumonia)with possible symptoms such as breathing difficulties and/or cough with or without fever;
• Decrease in the number of blood cells in the blood (thrombocytopenia)with the 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, feeling of general discomfort (nausea);
• Fever;
• Feeling of fatigue (fatigue);
• Weakness.

Common(may affect up to 1 in 10 people)

• Other types of blood cancer (myelodysplastic syndrome, acute myeloid leukemia). Most patients with these diseases were previously treated or at the same time or later with other cancer medicines (alkylating agents, topoisomerase inhibitors)or radiotherapy.
• Bone marrow 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 rashes;
• Swelling due to excessive fluid retention (edema);
• Inflammation of the mucous membranes of the digestive system from the mouth to the anus (mucositis);
• Chills;
• Feeling of general discomfort.

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

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

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

• Disorders of the lymphatic system due to a viral infection (virus-associated lymphoproliferative disorder);
• Coma;
• Seizures
• Agitation;
• Blindness;
• Inflammation or damage to the optic nerve (optic neuritis; optic neuropathy);
• Heart failure;
• Abnormal heart rhythms (arrhythmias).
• Skin cancer
• Skin and/or mucous membrane reaction with redness, inflammation, blisters, and tissue breakdown. (Lyell's syndrome, Stevens-Johnson syndrome).

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

Reporting of adverse effects

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

5. Storage of Fludarabina Accord

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

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

• Unopened vials

Store in a 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 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 must be used immediately. If it is 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.

For information for doctors and healthcare professionals, see section 6. Package contents and additional information.

Do not use this medicine if you notice any visible signs of deterioration.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package contents and additional information

Composition of Fludarabina Accord:

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

Fludarabina Accord is supplied in 2 ml glass vials.

Appearance of Fludarabina Accord and package contents:

Fludarabina Accord is a clear, colorless or slightly yellow-brown solution contained in a transparent glass vial.

Fludarabina Accord is available in three package sizes containing 1 vial, 5 vials, or 10 vials.

Not all package sizes may be marketed.

Marketing authorization holder:

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6ª planta

08039 Barcelona

Manufacturer:

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice

Poland

This medicine has been authorized in the following EEA countries with the following names:

Date of the last revision of this leaflet: May 2023

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS)http://www.aemps.gob.es

The following information is intended only for healthcare professionals

Fludarabina Accord, like other medicines with potential cytotoxicity, should be prepared by qualified personnel in a designated area. Handling and disposal procedures will be carried out in accordance with the guidelines used for cytotoxic medicines.

It is for intravenous use only.

Incompatibilities

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

Dilution

The required dose (calculated based on the patient's body surface area) is extracted into the syringe.

For intravenous bolus injection, this dose is further diluted with 10 ml of sodium chloride 9 mg/ml (0.9%). Alternatively, for perfusion, the required dose can be diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) and perfused 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

Marketing packaging: 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 must be used immediately. If it is 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, colorless, or slightly yellow-brown. It should be visually inspected before use.

Only transparent, colorless, or slightly yellow-brown solutions without particles should be used. Fludarabina Accord should not be used if the packaging is defective.

Handling and disposal

Fludarabina Accord should not be handled by pregnant women.

Appropriate handling and disposal procedures should be followed, which will be carried out in accordance with local requirements for cytotoxic medicines.

Caution should be exercised when handling and preparing the Fludarabina Accord solution. The use of latex gloves and safety glasses is recommended to avoid the risk of contact in the event of vial breakage or accidental spillage. If the solution comes into contact with the skin or mucous membranes, the affected area should be washed thoroughly with water and soap. In the event of eye contact, the eyes should be rinsed with plenty of water. Inhalation exposure should also be avoided.

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