BENEFLUR 10 mg FILM-COATED TABLETS

Introduction

Package Leaflet: Information for the User

Beneflur 10 mg Film-Coated Tablets

Fludarabine Phosphate

Read all of this leaflet carefully before you start taking 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 or pharmacist.
• 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 or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What Beneflur 10 mg film-coated tablets are and what they are used for
2. What you need to know before you take Beneflur 10 mg film-coated tablets
3. How to take Beneflur 10 mg film-coated tablets
4. Possible side effects
5. Storing Beneflur 10 mg film-coated tablets
6. Contents of the pack and other information

1. What Beneflur 10 mg film-coated tablets are and what they are used for

Beneflur 10 mg film-coated tablets contain the active substance fludarabine phosphate, which stops the growth of new cancer cells. All cells in the body produce new cells similar to themselves by dividing. Beneflur 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 normal disease-fighting functions and can displace healthy blood cells. This can result in infections, a decrease in the number of red blood cells (anemia), bruising, abnormal bleeding, or even organ failure.

Beneflur 10 mg film-coated tablets are used to treat B-cell chronic lymphocytic leukemia (B-CLL) in patients with sufficient production of healthy blood cells.

Treatment with Beneflur 10 mg film-coated tablets 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 take Beneflur 10 mg film-coated tablets

Do not take Beneflur 10 mg film-coated tablets:

• If you are allergic to fludarabine phosphate or any of the other ingredients of this medicine (listed in section 6).
• If you have severe kidney problems.
• If you are breastfeeding.
• If you have a low red blood cell count due 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 before taking Beneflur 10 mg film-coated tablets.

Warnings and precautions

Consult your doctor before starting treatment with Beneflur 10 mg film-coated tablets.

Be particularly careful with Beneflur 10 mg film-coated tablets:

• 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 bleedingthan usual after an injury, or if you seem to be getting many infections.

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

• Tell your doctor immediately.

These symptoms may be signs of a decrease in the number of blood cells, which can be caused by the disease itself or by treatment. It can last up to a year, regardless of whether you have received treatment with Beneflur 10 mg film-coated tablets before or not. During treatment with Beneflur 10 mg film-coated 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 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 Beneflur 10 mg film-coated tablets.

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

If Beneflur 10 mg film-coated tablets are used for a long period, their 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 Beneflur is used at the recommended dose, either after treatment with another medicine or at the same time as another medicine, the following adverse events have been reported:

neurological disorders manifesting as headache, feeling of dizziness (nausea) and vomiting, seizures, 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, 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 doses higher than the recommended dose of Beneflur, leukoencephalopathy (LE), toxic acute leukoencephalopathy (TAL), or reversible posterior leukoencephalopathy syndrome (PRES) have also been reported. The same symptoms of LE, TAL, or PRES described above may occur.

LE, TAL, and PRES can be irreversible, life-threatening, or fatal.

Whenever LE, TAL, or PRES are suspected, treatment with Beneflur will be stopped for further investigation. If the diagnosis of LE, TAL, or PRES is confirmed, your doctor will permanently stop your treatment with Beneflur.

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

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

• if you need to have your stem cells removedand you are being treated with Beneflur 10 mg film-coated tablets(or have been).

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

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

• if you notice any changes in your skin while taking this medicine or after finishing treatment.

• if you have or have had skin cancerit may worsen or recur during treatment with Beneflur 10 mg film-coated tablets or after treatment. You may develop skin cancer during or after treatment with Beneflur 10 mg film-coated tablets.

Other aspects to consider while taking Beneflur 10 mg film-coated tablets:

• If you are pregnant, you should not take Beneflur 10 mg film-coated tabletsunless your doctor clearly indicates it.

• Women: you should not become pregnant during treatment with Beneflur 10 mg film-coated tablets and should use an effective contraceptive methodduring treatment and for 6 months after finishing treatment, as Beneflur 10 mg film-coated tablets may be harmful to the fetus. If you become pregnant during treatment, you should inform your doctor immediately. Your doctor will decide with you whether you should continue taking Beneflur.

• Men: it is recommended not to father a child and to use an effective contraceptive methodduring treatment and for at least 3 months after finishing treatment. You should consult about sperm preservation before treatment because Beneflur 10 mg film-coated tablets may affect male fertility.

• You should not breastfeedwhile taking Beneflur 10 mg film-coated tablets.

• , as live organism vaccines should be avoided during treatment with Beneflur 10 mg film-coated tablets and after treatment.

• , you will regularly have blood tests and/or laboratory tests to monitor your kidney function. If your kidney problems are severe, this medicine will not be prescribed to you (see sections 2 and 3).

• Beneflur 10 mg film-coated tablets may cause more vomiting and nausea(feeling sick or queasy) than Beneflur administered intravenously. If this is a problem, your doctor may consider changing your treatment to intravenous Beneflur.

Children and adolescents

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

Elderly patients and Beneflur 10 mg film-coated tablets:

If you are over 65 years old, you will regularly have tests to check your kidney function (see also section 3. How to take Beneflur 10 mg film-coated tablets).

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

Other medicines and Beneflur 10 mg film-coated tablets

Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.

It is especially important to tell your doctor about:

• pentostatin (deoxicoformycin), also used to treat CLL-B. Taking these two drugs together may lead to severe lung complications.
• dipyridamole, used to prevent excessive blood clotting or similar substances. It may reduce the effectiveness of Beneflur 10 mg film-coated tablets.
• cytarabine (Ara-C), used to treat chronic lymphatic leukemia. If Beneflur 10 mg film-coated tablets are combined with cytarabine, the levels of the active form of Beneflur 10 mg film-coated tablets in leukemia cells may increase. However, it has not been shown that global levels in blood and their elimination from the blood have changed.

Pregnancy, breastfeeding, and fertility:

Pregnancy

Women: you should not become pregnant during treatment with Beneflur 10 mg film-coated tablets because animal studies and very limited human experience have shown a possible risk of fetal anomalies, as well as premature loss of pregnancy or premature birth. If you become pregnant during treatment, you should inform your doctor immediately. Your doctor will decide with you whether you should continue taking Beneflur.

Breastfeeding

You should not breastfeed while taking Beneflur 10 mg film-coated tablets.

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

Fertility in men and women

Women: you should use an effective contraceptive method during treatment and for 6 months after finishing treatment, as Beneflur 10 mg film-coated tablets may be harmful to the fetus.

Men: it is recommended not to father a child and to use an effective contraceptive method during treatment and for at least 3 months after finishing treatment. You should consult about sperm preservation before treatment because Beneflur 10 mg film-coated tablets may affect male fertility.

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

Driving and using machines

Some people may feel tired, weak, have vision changes, be confused, agitated, or have seizures while taking Beneflur 10 mg film-coated tablets. Do not attempt to drive or operate machinery until you are sure it does not affect you.

Beneflur 10 mg film-coated tablets contain lactose

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

Beneflur 10 mg film-coated tablets contain sodium

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

3. How to take Beneflur 10 mg film-coated tablets

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

How many tablets to take

The dose you should take depends 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 40 mg of fludarabine phosphate/m2 of body surface area, once a day. The normal dose is between 3 and 10 tablets per day. The exact number of tablets you should take is calculated by your doctor.

How to take Beneflur 10 mg film-coated tablets

Swallow the tablet whole with water. Do not break or chew the tablets. You can take Beneflur 10 mg film-coated tablets either on an empty stomach or with food.

How long to take Beneflur 10 mg film-coated tablets

Take the dose determined by your doctor once a day for 5 consecutive days.

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

The duration of treatment depends on the results obtained and tolerance to Beneflur 10 mg film-coated 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 your blood cell count and 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, the dose may be reduced.

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

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

If you take more Beneflur 10 mg film-coated tablets than you should

If you have taken too many tablets of Beneflur, tell your doctor immediately.

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

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

If you forget to take Beneflur 10 mg film-coated tablets

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

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

If you stop taking Beneflur 10 mg film-coated tablets

Do not stop taking Beneflur 10 mg film-coated tablets without your doctor's advice.

You and your doctor may decide to stop your treatment with Beneflur if side effects are becoming too severe.

If you have any further questions on 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 effects described below are, ask your doctor to explain them to you.

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

• 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 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 syndrome, Stevens-Johnson syndrome).

• if you have palpitations (if you suddenly become aware of your heartbeat) or chest pain. These may be signs of heart problems.

The following are possible adverse effects by frequency,based on the intravenous use of Beneflur.

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

• infections (some severe)
• infections due to a depressed immune system (opportunistic infections)
• lung infection (pneumonia)with possible symptoms such as breathing difficulties and/or cough with or without fever
• reduction in the number of platelets in the blood (thrombocytopenia)with the possibility of bruising and bleeding
• reduction in the number of white blood cells (neutropenia)
• reduction in the number of red blood cells (anemia)
• cough
• vomiting, diarrhea, feeling of general discomfort (nausea)
• fever
• feeling of fatigue (fatigue)
• weakness

Common adverse 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, at the same time, or later with other cancer drugs (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 mucous membrane lining 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 adverse effects(may affect up to 1 in 100 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 adverse effects(may affect up to 1 in 1,000 people)

• lymphatic system disorders 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
• heart rhythm disorders (arrhythmias)
• skin cancer
• skin and/or mucous membrane reaction with redness, inflammation, blisters, and tissue breakdown (Lyell syndrome, Stevens-Johnson syndrome)

Frequency not known(cannot be estimated from the available data)

• bleeding in the brain
• neurological disorders that manifest as 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 irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, toxic acute leukoencephalopathy, or posterior reversible leukoencephalopathy syndrome (PRLS)).
• bleeding in the lungs
• inflammation of the bladder, which can cause pain when urinating, and may cause blood in the urine (hemorrhagic cystitis)

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 that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Beneflur 10 mg film-coated tablets

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

Do not use this medicine after the expiration date that appears on the label of the bottle and the blister pack after "EXP". The expiration date is the last day of the month indicated.

Beneflur 10 mg tablets are a cytotoxic drug. It should always be stored in the original container, 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 thrown away through wastewater or household waste. Deposit the containers and medicines you no longer need at the SIGRE Point of the pharmacy. In case of doubt, ask your pharmacist how to dispose of the containers and medicines you no longer need. 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 tablets is carried out in accordance with local regulations for cytotoxic drugs.

6. Package contents and additional information

Composition ofBeneflur 10 mg tablets:

• The active ingredient is fludarabine phosphate. Each film-coated tablet contains 10 mg of fludarabine phosphate.

• The other ingredients are:

• In the core of the tablet: microcrystalline cellulose, lactose monohydrate, anhydrous colloidal 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 package contents:

Beneflur 10 mg tablets are oblong, salmon-colored tablets marked with "LN" in a regular hexagon on one side.

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

Beneflur 10 mg tablets are available in packages containing:

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

Only some package sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Sanofi B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

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

This prospectus was approved in July 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