Prospect: information for the user

Beneflur 10 mg film-coated tablets

Fludarabine phosphate

Read this prospect carefully before starting to take this medicine, as it contains important information for you.

• Keep this prospect, as you may need to read it again.
  If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed to you alone, and you must not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this prospect. See section 4.

1. What isBeneflur 10 mg tabletsand for what it is used

2. What you need to know before starting to takeBeneflur 10 mg tablets

3. How to takeBeneflur 10 mg tablets

4. Possible adverse effects

5. Storage ofBeneflur 10 mg tablets

6. Contents of the package and additional information

Beneflur 10 mg tabletscontain the active substance fludarabine phosphate that stops the growth of new cancer cells.All cells in the body produce new cells similar to themselves through division.Benefluris 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 carrying out 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, abnormally severe bleeding or even organ failure.

Beneflur 10 mg tabletsare 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 Beneflur 10 mg tablets should only be initiated in patients with advanced disease who present symptoms related to the disease or evidence of disease progression.

Do not take Beneflur 10 mg tablets:

• If you are allergic to fludarabine phosphate or any of the components of this medication (listed in section 6).
• If you have severe kidney problems.
• If you are breastfeeding.
• If you have a low number of red blood cells due to a certain type of anemia (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 before taking Beneflur 10 mg tablets.

Warnings and precautions:

Consult your doctor before starting to take Beneflur 10 mg tablets.

Be especially careful with Beneflur 10 mg tablets:

• if your bone marrow does not function properly or if your immune system does not function well or is depressed or has 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, observe 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 if you have a rash or blister on your skin.

• Inform your doctor immediately.

These symptoms may be signs of a decrease in the number of blood cells, which may be caused by the disease itself or by the treatment. This may last up to a year, regardless of whether you have received treatment with Beneflur 10 mg tablets before or not. During treatment with Beneflur 10 mg tablets, your immune system may also attack different parts of your body, or your red blood cells (known as "autoimmune phenomena"). These problems can be life-threatening.

If this occurs, your doctor will interrupt treatment and you may receive other medications, 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 Beneflur 10 mg tablets.

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

Beneflur 10 mg tablets have not been studied for long-term use, and 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 Beneflur is used at the recommended dose, after treatment with another medication or at the same time as another medication, the following adverse events have been reported:

neurological disorders that manifest as headache, dizziness (nausea), and 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 irreversible partial or complete 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.Leukoencephalopathy (LE), acute toxic leukoencephalopathy (LTA), or reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported in patients treated with doses higher than the recommended dose of Beneflur. The same symptoms of LE, LTA, or RPLS described above may occur.

LE, LTA, and RPLS can be irreversible, life-threatening, or fatal.

Each time LE, LTA, or RPLS is suspected, treatment with Beneflur will be stopped for further investigation. If LE, LTA, or RPLS is confirmed, your doctor will permanently discontinue treatment with Beneflur.

-if you notice any pain in the side, blood in the urine, or a decrease in urine output.

When your disease is very severe, your body may not be able to eliminate all the waste products from the cells destroyed by Beneflur. This is called "tumor lysis syndrome" and can cause kidney failure and heart problems from the first week of treatment. Your doctor is aware of this and may give you other medications to prevent it. They may decide that your treatment should start in the hospital.

• if you need to have stem cells extracted and are being treated with Beneflur 10 mg tablets (or have been).

• if you need a blood transfusion and are being treated with Beneflur 10 mg tablets (or have been).

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

• if you observe any change in the skin while receiving this medication or after treatment has ended.

• if you have or have had skin cancer, it may worsen or recur during treatment with Beneflur 10 mg tablets or after treatment has ended. You may develop skin cancer during or after treatment with Beneflur 10 mg tablets.

Other aspects to consider while being treated with Beneflur 10 mg tablets:

• If you are pregnant, do not take Beneflur 10 mg tablets unless your doctor clearly indicates it.

• Women: Do not become pregnant during treatment with Beneflur 10 mg tablets and use an effective contraceptive method during treatment and for 6 months after treatment ends, as Beneflur 10 mg tablets may be harmful to the fetus. If pregnancy occurs during your treatment, inform your doctor immediately. Your doctor will decide with you whether to continue taking Beneflur.

• Men: It is recommended not to father a child and use an effective contraceptive method during treatment and for at least 3 months after treatment ends. You should consult about sperm preservation before treatment, as Beneflur 10 mg tablets may alter male fertility.

• Do not breastfeed while being treated with Beneflur 10 mg tablets.

• if you need a vaccine, consult your doctor, as live vaccines should be avoided during treatment with Beneflur 10 mg tablets and after treatment has ended.

• if you have kidney problems or are over 65 years old, regular blood tests and/or laboratory tests will be performed to monitor kidney function. If your kidney problems are severe, this medication will not be prescribed (see sections 2 and 3).

• Beneflur 10 mg tablets may cause more vomiting and nausea (feeling dizzy or sick) than intravenous Beneflur. If this is a problem, your doctor may consider switching to intravenous Beneflur.

Children and adolescents:

The safety and efficacy of Beneflur 10 mg tablets in children under 18 years have not been established. Therefore, the use of Beneflur 10 mg tablets is not recommended in children.

Older patients and Beneflur 10 mg tablets:

If you are over 65 years old, regular kidney function tests will be performed (see also section 3. How to take Beneflur 10 mg tablets).

If you are over 75 years old, you will be closely monitored.

Other medications and Beneflur 10 mg tablets:

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

It is especially important to inform your doctor about:

• pentostatin (deoxycoformycin)also used to treat CLL-B. Taking these two medications together may lead to severe pulmonary complications.
• dipyridamole, used to prevent excessive blood clotting or other similar substances. It may reduce the effectiveness ofBeneflur 10 mg tablets.
• citarabine(Ara-C) used to treat chronic lymphocytic leukemia. IfBeneflur 10 mg tabletsare combined with citarabine, they may increase the levels of the active form ofBeneflur 10 mg tabletsin leukemic cells. However, it has not been shown that global levels in the blood and their elimination from the blood have changed.

Pregnancy, breastfeeding, and fertility:

Pregnancy

Women: Do not become pregnant during treatment with Beneflur 10 mg tablets, as studies in animals and very limited human experience have shown a possible risk of fetal abnormalities, as well as premature loss of pregnancy or premature birth. If pregnancy occurs during your treatment, inform your doctor immediately. Your doctor will decide with you whether to continue taking Beneflur.

Breastfeeding

Do not breastfeed while being treated with Beneflur.

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

Fertility in men and women

Women: Use an effective contraceptive method during treatment and for 6 months after treatment ends, as Beneflur 10 mg tablets may be harmful to the fetus.

Men: It is recommended not to father a child and use an effective contraceptive method during treatment and for at least 3 months after treatment ends. You should consult about sperm preservation before treatment, as Beneflur 10 mg tablets may alter male fertility.

Before starting treatment with Beneflur, it is recommended that both men and women who plan to have a child after treatment speak with a doctor.

Driving and operating machinery:

Some people may feel tired, weak, have visual disturbances, be confused, agitated, or have convulsions while receiving treatment withBeneflur 10 mg tablets.Do not attempt to drive or operate machinery until you are sure it does not affect you.

Beneflur 10 mg tablets contain lactose

This medication contains lactose (a type of sugar). If your doctor has told you that you have an intolerance to certain sugars, consult with them before taking this medication.

Beneflur 10 mg tablets contain sodium

This medication contains less than 1 mmol (23 mg) of sodium per tablet, which is essentially "sodium-free".

Always takethis medicationexactly as your doctor has told you. Consult your doctor or pharmacist if you are unsure.

How many tablets should you take

The dose you should take depends on your body surface area. Thisis measured in square meters(m2),andis determined by your doctor from your height and weight.

The recommended dose is 40mg of fludarabine phosphate/m2of body surface area, once a day.The usual dose is between 3 and 10 tablets a day.The exact number of tablets you should take is calculated by your doctor.

How to take Fludarabine 10 mg tablets

Swallow the tablet whole with water. Do not break or chew the tablets. You can take Fludarabine 10 mg tablets either with an empty stomach or with food.

For how long should you takeFludarabine 10 mg tablets

Take the dose determined by your doctoronce a dayfor 5consecutive days..

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

The duration of treatmentdepends on the results obtained and the tolerance toFludarabine 10 mg tablets.The next cycle may be delayed if side effects are a problem.

You will have regular blood tests during treatment.Your individual dose will be carefully adjusted according to the number of your blood cells and your response to treatment. If your blood cell count is too low, your next treatment cycle may be postponed for up to two weeks or your dose may be reduced. If side effects are a problem, your dose may be reduced.

If you have been treated for two cycles and have not responded to treatmentbut have shown few symptoms of a decrease in the number of blood cells, your doctor may decide to increase the dose.

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

If you take more Fludarabine 10 mg tablets than you should

If you have taken too many tablets ofFludarabine, inform your doctor immediately.

High doses may also cause a severely reduced number of blood cells.

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

If you forget to take Fludarabine 10 mg tablets

If you think you may have forgotten a dose or vomit after taking the tablet, talk to your doctor as soon as possible.

Do not take a double dose to make up for the missed tablets.

If you stop usingFludarabine 10 mg tablets

Do not stop takingFludarabine 10 mg tablets without consulting your doctor.

You and your doctor may decide to stop your treatment withFludarabineif side 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 side effects are described below, ask your doctor to explain them to you.

Some side effects can be life-threatening.Consult your doctor immediately:

-if you have difficulty breathing, coughing, or 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 severe infections caused by organisms that normally do not cause diseases in healthy people (opportunistic infections), including late reactivation of viruses, such as herpes zoster.(opportunistic infections)including late reactivation of viruses, such as herpes zoster.

• if you notice any pain in the side, blood in the urine, or decreased urine output. These may be signs oftumor 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 signsof 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.

Below are the possible side effects according to their frequency,from the intravenous use of Beneflur.

Frequent side effects(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 difficulty breathing and/or coughing with or without fever
• reduction in the number of platelets in the blood(thrombocytopenia)with a possibility ofbruising and bleeding
• reduction in the number of white blood cells(neutropenia)
• reduction in the number of red blood cells(anemia)
• coughing
• vomiting, diarrhea,general feeling of discomfort(nausea)
• fever
• feeling of fatigue(fatigue)
• weakness

Common side effects(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, simultaneously or later with other cancer drugs(alkylating agents, topoisomerase inhibitors)or radiation therapy
• medullary depression(myelosuppression)
• severe loss of appetite leading to weight loss (anorexia)
• numbness or weakness in the limbs (peripheral neuropathy)
• altered vision
• inflammation of the mucous membranes 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

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

• autoimmune disorder (see section 2)
• tumor lysis syndrome (see section 2)
• confusion
• pulmonary toxicity; scarring of 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 side effects(may affect up to 1 in 1,000 people)

• lymphatic system disorders due to viral infection(lymphoproliferative disorder associated with VEB)
• coma
• convulsions
• agitation
• blindness
• inflammation or damage to the optic nerve (optic neuritis; optic neuropathy)
• heart failure
• alterations in heart rhythm(arrhythmias)
• skin cancer
• reaction in theskin and/or mucous membrane with redness, inflammation, blisters, and tissue rupture (Stevens-Johnson syndrome, Lyell syndrome)

Unknown frequency(cannot be estimated from available data)

• bleeding in the brain
• neurological disorders manifesting as headache, dizziness (nausea), vomiting, convulsions, visual disturbances including loss of vision, changes in mental state (abnormal thinking, confusion, altered consciousness), and occasionally neuromuscular disorders manifesting as muscle weakness in the limbs (including irreversible partial or complete paralysis) (symptoms ofleucoencephalopathy, acute toxic leucoencephalopathy, or reversible posterior leucoencephalopathy syndrome (RPLS)).
• bleeding in the lungs
• inflammation of the bladder, which may cause pain while urinating, and may cause blood in the urine (hemorrhagic cystitis)

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report themdirectly through theSpanish System for the Pharmacovigilance of Medicines for Human Use:www.notificaram.es.By reporting side effects, 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 label of the bottle and the ampoule label after “CAD”. The expiration date is the last day of the month indicated.

Beneflur 10 mg tabletsis a cytotoxic drug. It must be stored always in the original safety packaging, child-resistant.

Do not store at a temperature above 25°C. Do not refrigerate. Store in the original packaging to protect it from moisture.

Medicines should not be disposed of through drains or in the trash. Deposit the containers and medicines you no longer need at the SIGRE collection pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the containers and medicines you no longer need. In this way, you will help protect the environment.

Return any unused tablets to your doctor or pharmacist. They will ensure that the disposal of Beneflur 10 mg tabletsis carried out in accordance with local regulations for cytotoxic drugs.

Composition ofBeneflur 10 mg tablets:

• The active ingredient isfludarabine phosphate.Each coated tablet contains 10mg offludarabine phosphate.

• The other components are:

-In the tablet core:microcrystalline cellulose, lactose (monohydrate), colloidal anhydrous silica, sodium croscarmellose, magnesium stearate;

-In the coating:hypromellose, talc, titanium dioxide (E171), iron oxide pigment (yellow (E172)), iron oxide pigment (red (E172)).

Appearance ofBeneflur 10mg tablets and contents of the package:

Beneflur 10 mg tabletsare oblong tablets of salmon color marked on one face with “LN” in a regular hexagon.

The tablets are presented in blisters of 5 tablets each. The blisters are made of thermoplastic polyamide/aluminum/polypropylene with an aluminum foil cover. The blisters are included in a polyethylene bottle with a polypropylene child-resistant cap.

Beneflur 10 mg tablets are available in packages that contain:

• 15tabletsin 3 blisters in a child-resistant safety bottle.
• 20tabletsin 4 blisters in a child-resistant safety bottle.

Only some package sizes may be marketed.

Marketing authorization holder and responsible manufacturer

Marketing authorization holder

Sanofi B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

Responsible manufacturer

EUROAPI UK Limited, 37 Hollands Road, Haverhill,Suffolk,CB9 8PU, United Kingdom

Or

SANOFI WINTHROP INDUSTRIE, 30-36, avenue Gustave Eiffel,37100 Tours, France

Local representative

sanofi-aventis, S.A.

C/ Rosselló i Porcel, 21

08016 Barcelona

Spain

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

This leaflet was last approved in July 2023

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